Novel orally active iron (III) chelators

ABSTRACT

A novel 3-hydroxypyridinone compound of formula I is provided  
                 
 
     wherein R is hydrogen or a group that is removed by metabolism in vivo to provide the free hydroxy compound,  
     R 1  is an aliphatic hydrocarbon group or an aliphatic hydrocarbon group substituted by a hydroxy group or a carboxylic acid ester, sulpho acid ester or a C 1-6  alkoxy, C 6  -aryloxy or C 7-10  aralkoxy ether thereof,  
     R 3  is selected from hydrogen and C 1-6  alkyl;  
     and R 4  is selected from hydrogen, C 1-6  alkyl and a group as described for R 2  ;  
     characterized in that  
     R 2  is selected from groups  
     (i) —CONH—R 5    
     (ii) —CH 2 NHCO—R 5    
     (iii) —SO 2 NH—R 5    
     (iv) —CH 2 NHSO 2 —R 5    
     (v) —CR 6 R 6 OR 7    
     (viii) —CONHCOR 5    
     wherein R 5  is selected from hydrogen and optionally hydroxy, alkoxy, or aralkoxy substituted C 1-13  alkyl, aryl and C 7-13  aralkyl,  
     R 6  is independently selected from hydrogen, C 1-13  alkyl, aryl and C 7-13  aralkyl,  
     and R 7  is selected from hydrogen, C 1-13  alkyl, aryl and C 7-13  aralkyl or a pharmaceutically acceptable salt of any such compound  
     with the proviso that when R 7  is hydrogen, R 6  is not selected from aryl and with the proviso that the compound is not 1-ethyl-2-(1′-hydroxyethyl)-3-hydroxypyridin-4-one.

[0001] The present invention relates to novel compounds having activityas orally active iron chelators, to pharmaceutical compositionscontaining these and to their use in treating disorders associated withiron distribution, particular disorders involving excess of iron andpresence of iron dependent parasites.

[0002] Members of the hydroxypyridone class are well known for theirability to chelate iron in physiological environment and these havereported as useful in treating iron related disorders such asthalassaemia and, when complexed with iron, anaemia. For example, seeU.S. Pat. Nos. 4,840,958, 5,480,894 and Hider et al (1996 ) ActaHaematologica 95:6 -12. By virtue of their low molecular weight and highaffinity for iron (III) these compounds now provide the possibility ofremoving iron from iron overloaded patients with the hope of providingoral activity. Related compounds for such use are disclosed in U.S. Pat.No. 4,585,780 wherein the characteristics required for oral activity arediscussed further.

[0003] Two particular compounds referred to by Hider et al, CP20 andCP94 (see Tables 1 and 2 herein), have proved to be effective in man,but both have disadvantages in that they are rapidly inactivated byphase II metabolism and are able to cross the placenta and blood brainbarrier. The extensive biotransformation of these compounds is reflectedby their limited ability to mobilise excess body iron in thalassaemicpatients.

[0004] The requirements for orally active chelators are set out in Table4 of Hider et al as (i) good absorption from the gastrointestinal tract,(ii) efficient liver extraction, (iii) poor entry into peripheral cellssuch as thymus, muscle, heart and bone marrow and (iv) poor ability topenetrate the blood-brain barrier and maternal/placental barriers. Thisreference refers to desired partition coefficients (K_(part)), hereinreferred to as distribution coefficient values (D_(pH7.4)), for theseproperties as (i)>0.2, (ii)>1.0, (iii)<0.001 and (iv)<0.001,respectively rendering one compound seemingly unsuited to satisfying allfour criteria. Hider et suggest the pro-drug strategy to be one possibleroute forward but no specific compounds have so far been found to meetall criteria.

[0005] Pivalic acid esters of hydroxyalkyl substituted 3-hydroxypyridin-4 -ones have been studied as pro-drugs and found to leadto efficient excretion of iron, in bile and urine, but as reported byHider et al these are now thought to potentially interfere with thecarnitine cycle and thus may not be suitable for use in regular and/orlarge doses in man.

[0006] It is known that the 2-(1′-hydroxyethyl) metabolite of1,2-diethyl-3-hydroxypyridin-4-one (CP94) produced in rat is an activeiron chelator (see Singh et al (1992) Drug Metabolism and DispositionVol 20.No 2,page 256-261). EP 0494754 A proposes 1-hydroxyethyl as oneof many possible substituents at any of the pyridin-4-one positions 1,2, 5 or 6 for use as iron chelator in treatment of malaria; none ofthese compounds are however exemplified as made or tested for activity.EP 0768302 A (Novartis) describes a series of related3-hydroxypyridin-4-ones in which the 2-position is substituted by amethyl group which carries an optionally substituted phenyl or heteroylring and a free or esterified hydroxy group. The phenyl or heteroylgroup is taught as an essential element of these compounds.

[0007] The present inventors now have provided a group of3-hydroxypyridin-4-one iron chelators having improved properties ascompared to the prior art as assessed against the criteria set outabove. The preferred compounds of the invention are all characterised bymeeting a further criterion (v) in so far as they have a pM for IronIII, i.e. affinity for iron as Fe III, of at least 20, preferably inexcess of 23. Preferred compounds have efficiency of iron mobilisationof in excess of 52% when given orally to rats. The definition of pM usedherein is the concentration of ferric ion in solution when the totalamount of iron equals 10⁻⁶ M and the concentration of ligand is 10⁻⁵Mand pH is 7.4.

[0008] The present compounds offer the prospect of effectivepharmaceutical formulations having reduced levels of active agent, withparticular properties of selective targeting of the chelating activityto tissues where the iron level requires alteration, particularly theliver. A particular property of preferred compounds of the invention isthat they are not significantly metabolised through conjugation and, inpreferred forms, are provided as prodrugs.

[0009] Thus in a first aspect of the present invention there is provideda novel 3-hydroxypyridin-4-one compound of formula I

[0010] wherein R is hydrogen or a group that is removed by metabolism invivo to provide the free hydroxy compound,

[0011] R¹is an aliphatic hydrocarbon group or an aliphatic hydrocarbongroup substituted by a hydroxy group or a carboxylic acid ester, sulphoacid ester or a C₁₋₆ alkoxy or C₇₋₁₀aryloxy or aralkyloxy ether thereof,

[0012] R³is selected from hydrogen and C₁₋₆alkyl;

[0013] and R⁴is selected from hydrogen, C₁₋₆alkyl and a group asdescribed for R²;

[0014] characterized in that

[0015] R²is selected from groups

[0016] (i) —CONH—R⁵

[0017] (ii) —CH₂NHCO—R⁵

[0018] (iii) —SO₂NH—R⁵

[0019] (iv) —CH₂NHSO₂—R⁵

[0020] (v) —CR⁶R⁶OR⁷

[0021] (viii) —CONHCOR⁵

[0022] wherein R⁵is selected from hydrogen and optionally hydroxy,alkoxy, aryloxy or aralkoxy substituted C₁₋₁₃ alkyl, aryl and C₁₋₁₃aralkyl,

[0023] R⁶is independently selected at each occurrence from hydrogen,C₁₋₁₃ alkyl, aryl and C₇₋₁₃ aralkyl,

[0024] and R⁷ is selected from hydrogen, C₁₋₁₃alkyl, aryl andC₇₋₁₃aralkyl or a pharmaceutically acceptable salt of any such compound

[0025] with the proviso that when R⁷ is hydrogen, R⁶is not selected fromaryl.

[0026] and with the proviso that the compound is not1-ethyl-2-(1′-hydroxyethyl)-3-hydroxypyrid-4-one

[0027] Preferably at least one of R, R¹or R⁷ is such as to form a3-ester or ether prodrug. Those skilled in the art will recognise theterm 3-ester or ether prodrug to mean compounds wherein the 3-hydroxygroup has been esterified with a carboxylic or sulpho acid, or formedinto an ether with a C₁₋₆alkyl or C₁₋₁₀aralkyl group which is removed invivo to provide the free hydroxy compound. Typically such carboxylicacid esters or ethers are of C₁₋₇ type, ie. the 3-substituent is —O—R⁸or —OC(O)—R⁸ where R⁸ is C₁₋₆alkyl or C₁₋₁₀aralkyl.

[0028] More preferably R⁵and R⁷ are independently selected from C₁₋₆alkyl, aryl or aralkyl, e.g. benzyl, which may be substitued withC₁₋₆alkoxy. More preferably R⁶ is independently selected from hydrogenor C₁₋₆ alkyl.

[0029] The positions 5 and 6 are preferably unsubstituted, ie. R³ and R⁴are preferably hydrogen, but may be substituted with conventionalpyridin-4-one substituents as disclosed by the prior art as suitable iniron chelators.

[0030] Where R¹ is an aliphatic carbon group substituted by hydroxy andthat hydroxy is esterified the ester acyl group is preferably of formula—CO—R⁹ where R⁹ is C₁₋₆ alkyl or C₁₋₁₀ aryl, more preferably being—CO-Phenyl or —CO-hetero, eg. heterocylic rings with one of two nitrogenmembers and three to five carbons.

[0031] R¹ and R⁵ are conveniently independently selected C₁₋₆alkyl,preferably methyl or ethyl, but preferably may be a hydroxy, alkoxy oresterified hydroxy terminated C₁₋₆alkyl group. Where R¹ is a hydroxyterminated alkyl it is advantageous that the alkyl group is of 3 to 6carbons long, more preferably being 3 carbons long, e.g. where R¹ is—(CH₂)₃—OH, as such compounds are known to be metabolised in vivo to thecorresponding —(CH₂)₂—CO₂H derivative with consequent advantages of lowD_(pH7.4) after metabolism, e.g. in the liver.

[0032] Most preferred compounds are of the type where R² is of groups(i),or (v).

[0033] More preferably R²is a group —CR⁶R⁶OR⁷ wherein R⁶ isindependently selected at each occurrence from hydrogen, C₁₋₁₃alkyl orC₆aryl and R⁷ is C₁₋₆alkyl, more preferably methyl or ethyl. Analternate preferred group for R² is —CONH—R⁵.

[0034] Still more preferred compounds of the invention have a D_(pH7.4)as determined in an octanol/MOPS pH 7.4 system of in excess of 1, morepreferably being metabolised in vivo to a metabolite having a D_(pH7.4)of less than 1, more preferably less than 0.1 and still more preferablyless than 0.001, as set out in the criteria above.

[0035] A second aspect of the present invention provides processes forpreparation of new compounds of the invention, a third provides novelintermediates for use in these processes, a fourth provides the use ofthe compounds in therapy, a fifth provides their use in manufacture ofmedicaments and a sixth provides pharmaceutical compositions comprisingthem.

[0036] The process of the invention is broadly that as set out in anyone or more of Schemes 1, 2, 3 and 4. The preferred process comprisesall relevant steps of these schemes for a given compound of theinvention. Those skilled in the art will readily produce free compoundsfrom the salts shown by conventional techniques.

[0037] Novel intermediates of the invention are of formula (IIb), (IIc)and (III) of Scheme I (IVa), (IVb) and (IVc) of Scheme 2, (VI), (VII)and (VIII) of Scheme 3 and (X), (XI), (XII) of Scheme 4.

[0038] Thus a first process of the invention comprises the reaction of a2-(1′-hydroxyalkyl)-3-hydroxy-pyran-4(1H)-one of formula (IIa)

[0039] where R¹⁰ is a group as defined in R⁶

[0040] with benzaldehyde dimethyl acetal to provide the corresponding8-oxo-4,8-dihydro-2-phenyl-4H[3,2-d]-m-dioxin of formula (IIb),

[0041] reacting that compound with a compound R¹NH₂ to give thecorresponding pyridino dioxin of formula (IIc)

[0042] and reducing that with hydrogen to give the corresponding2-hydroxyalkyl-pyridin-4(1H)-one.

[0043] A second process of the invention comprises the protection of the3-hydroxyl group of a 2-(1′-hydroxyalkyl)-3-hydroxy-pyran-4(1H)-one offormula (IV),

[0044] eg. using a benzyl halide, preferably benzyl bromide to give acompound (IVa)

[0045] alkylating the 2-(1′-hydroxy) group, eg. with an alkyl halidesuch as alkyl iodide to, reacting the product thereof (IVb)

[0046] with a compound R¹NH₂ to provide the corresponding2-hydroxyalkyl-pyridin-4(1H)-one (IVc)

[0047] and reducing that to provide the correpsonding unprotectedcompound.

[0048] A third process of the present invention reacts a2-carboxyl-3-benzoyloxy-pyran-4(1H)-one of formula (IXd),, thatoptionally being provied by oxidising the corresponding formyl compound(IXc) eg. with sulfamic acid and sodium chlorite,

[0049] with mercaptothiazoline, eg. in the presence ofdicyclocarbodiimide and dimethylaminopyridine to provide thecorresponding 2-carbonyl-thiazolidine-2-thione of formula (X),

[0050] reacts that with a compound R⁵NH₂ to give the corresponding2-amido compound of of formula (XI),

[0051] reacting that with a compound R¹NH₂ to give the corresponding2-amido-pyridin-4(1H)-one compound of formula (XII)

[0052] and optionally reducing that to provide the corresponding2-hydroxyalkyl-pyridin-4(1H-one.

[0053] Novel intermediates are the8-oxo-4,8-dihydro-2-phenyl-4H[3,2-d]-m-dioxins,2-(1-alkoxyoxyalkyl)-3-hydroxy-pyran-4(1H)-ones and corresponding2-carbonyl-thiazolidine-2-thiones corresponding to the compounds ofFormula I.

[0054] Also provided within formula (I) are novel compounds which aremetabolites of the preferred prodrug compounds of the first aspect ofthe invention but which have D_(pH7.4) less than 1; these also beingactive iron III chelating agents once the compounds of the first aspecthave been metabolised eg. in the liver, to remove any ether or esterprotecting group where that was required to provide a D_(pH7.4) of 1 orabove. For example in compound CP362below, the methyl group (R informula I above), is removed in vivo resulting in a drop in D_(pH7.4) togive the compound of formula I wherein R is hydrogen, R² is CH(OH)CH₃,R¹ is ethyl and R³ and R⁴ are hydrogen. This compound1-ethyl-2-(1′-hydroxyethyl)-3-hydroxypyrid-4-one is known.

[0055] Those skilled in the art will readily appreciate that some ofthese compounds will be known already, but in so far as compounds arenovel they are also rendered inventive Particularly provided is theprovision of such metabolites ‘for use in therapy’ eg. ‘for use intherapy of iron related disorders’. These compounds, while not of idealD_(pH7.4) for oral activity, will still be of potential use byparenteral or other route of administration.

[0056] Salts of the compounds of the invention may readily be formed byreaction of the compound with the appropriate base or acid undersuitable conditions. Zwitterionic forms, where appropriate, mayconveniently be obtained by freeze drying an aqueous solution at aselected pH. Freeze drying of an aqueous solution whose pH has beenadjusted to 7.0 or to greater than 9.0 with the desired base provides aconvenient route to a salt of that base. Salts with acids mayconveniently be obtained by recrystallization of the compound of formula(1) from an aqueous/organic solution, for example the hydrochloridebeing obtained on recrystallization from a dilute hydrochloricacid/ethanol solution.

[0057] Pro-drugs may be formed by reaction of any free hydroxy groupcompound of formula (I) or a derivative thereof with the appropriatereagent, in particular with an organic acid or derivative thereof, forexample as described in U.S. Pat. No. 4,908,371 and/or with an alcoholor phenol, for example using standard esterification procedures.

[0058] The compounds of formula (I) may be formulated with aphysiologically acceptable diluent or carrier for use as pharmaceuticalsfor veterinary, for example in a mammalian context, and particularly forhuman use, by a variety of methods. For instance, they may be applied asa composition incorporating a liquid diluent or carrier, for example anaqueous or oily solution, suspension or emulsion, which may often beemployed in injectable form for parenteral administration and thereforemay conveniently be sterile and pyrogen free. Oral administration ispreferred for the preferred compounds of the invention. Althoughcompositions for this purpose may incorporate a liquid diluent orcarrier, it is more usual to use a solid, for example a conventionalsolid carrier material such as starch, lactose, dextrin or magnesiumstearate. Such solid compositions may conveniently be of a formed type,for example as tablets, capsules (including spansules), etc.

[0059] Other forms of administration than by injection or through theoral route may also be considered in both human and veterinary contexts,for example the use of suppositories or pessaries. Another form ofpharamceutical composition is one for buccal or nasal administration,for example lozenges, nose drops or an aerosol spray. Thus, theinvention further includes a pharmaceutical composition comprising a3-hydroxypyridin-4-one drug or prodrug of formula (I) as definedhereinbefore together with a physiologically acceptable diluent orcarrier.

[0060] Compositions may be formulated in unit dosage form, i.e. in theform of discrete portions each comprising a unit dose, or a multiple orsub-multiple of a unit dose. The dosage of active compound given willdepend on various factors, including the particular compound employed inthe composition and the mode of administration and type of disease betreated, eg. whether for iron overload as in thalessemia or for use intreating iron dependent parasites eg. malaria

[0061] Typical dosages for use in human therapy will usually lie in theregion of about 0.1 to 50 g daily, preferably 0.5 g to 20 g daily,particularly from about 1 or 2 g to 10 or 15 g daily, for example about5 g, veterinary doses being on a similar g/kg body weight ratio.However, it will be appreciated that it may be appropriate under certaincircumstances to give daily dosages either below or above these levels.Where desired, more than one compound according to the present inventionmay be administered in the pharmaceutical composition, when the totaldosage will usually correspond to those discussed above, or, indeed,other active compounds may be included in the composition.

[0062] The present invention will now be described by way ofillustration only by reference to the following non-limiting Examples,Tables, Schemes and Figures. Further examples of the invention willoccur to those skilled in the art in the light of these.

TABLES

[0063] Table 1: shows compound codes, structures, D_(pH7.4) (also knownas Kpart), pKa, Logβ3, pM and in vivo iron mobilisation data forcompounds of the invention where R² is of type (v), both active agentsfor oral administration and their metabolites, the latter being suitablefor parenteral or other non-oral route administration.

[0064] Table 2: summarises Table 1 with significant pKa2 and comparativedata added.

[0065] Table 3: shows compound codes structures, D_(pH7.4) (also knownas Kpart), pKa, Logβ3, pM and in vivo iron mobilisation data forcompounds of the invention where R² is of type (i).

SCHEMES

[0066] Scheme 1 shows the reaction scheme for synthesis of novelintermediates from compounds of formula (IIa) to compounds of formula(III)

[0067] Scheme 2 shows the reaction scheme for synthesis of novelintermediates from compounds (IV) to orally active compounds (V) and

[0068] Scheme 3 shows the reaction scheme for formation of R¹ ester typeoral active compounds.

[0069] Scheme 4 shows the reaction scheme for synthesis of novelintermediates from compounds (IX) to amide products (XII) and (XIII).

FIGURES

[0070]FIG. 1 shows a speciation plot of ratio of ligand to Iron (III) vpH.

[0071]FIG. 2 shows in vivo iron mobilisation using the metabolite freehydroxy compounds of the invention.

[0072]FIG. 3 shows in vivo iron mobilisation using the orally activeether compounds of the invention.

SYNTHESIS

[0073] Known Intermediates

[0074] 2,5-Dihydro-2,5-dimethoxy-2-furanmethanol: Produced by the methodof Achamatowicz et al (1971) Tetrahedron; 27: 1973-1996.Distillation at78° C./0.5 mmHg (Lit. ^((a))71° C./1.0 mmHg; gave the title compound(177 g, 73.8%) as colorless liquid. Evaporation of the solvent anddistillation at 74° C./0.4 mmHg gave title product as colorless liquid.(115.5 g, 72.2%).

[0075] 6-Methoxy-2H-pyran-3(6H)-one: Produced by the method of ofAchamatowicz et al (1971). Distillation at 47˜48° C./0.5 mmHg (lit.76˜81° C./13 mmHg) afforded a clear, sharp-smelling oil.

[0076] Novel Intermediate

[0077] 4-Bromo-6-methoxy-2H-pyran-3(6H)-one.

[0078] To a solution of 6-methoxy-2H-pyran-3(6H)-one 12.8(0.1 mole) in40 ml CH₂Cl₂at 0° C. was added 16.0 g (0.1 mole) of bromine in 10 ml ofCH₂Cl₂. Then 14 ml of triethylamine was added dropwise at 0° C. and thereaction was allowed to warm to room temperature and stir for two hours.The reaction was then diluted with 200 ml of toluene. After filtration,the organic solution was then washed with 5% NAHCO₃ and brine, driedwith Na₂SO₄, filtered and concentrated to yield the crude product aslight brown solid. Recrystallisation from ethyl acetate afforded thetitle compound (17 g, 82%) as a white crystalline solid. m.p. 74-75° C.¹H-NMR (CDCl₃) δ:_(—)3.5(s, 3H, OCH₃), 4.4(q, 2H, 2,2′-H, AB center,J_(22′)=14.5 Hz, AEδ_(22′)=18.5 Hz), 5.05(d, 1H, 6-H), 7.25(d, 1H, 5-H)Anal. Calcd. for C₆H₇O₃Br: C, 34.81; H, 3.41%. Found: C, 35.03; H, 3.45%Recrystallisation from ethyl acetate afforded the title compound (17 g,82%) as a white crystalline solid. m.p. 74-75° C. Anal. Calcd. forC₆H₇O₃Br: C, 34.81; H, 3.41%. Found: C, 35.03; H, 3.45%

[0079] Known Intermediates

[0080] 3-Hydroxy-pyran-4(1H)-one (pyromeconic acid)

[0081] The solid was treated with activated carbon and recrystallisedfrom toluene to yield the title compound (2.5 g, 80%) as a light yellowplates. m.p. 114-115° C. [lit. 113-115.5° C. (Tate and Miller., 1964)U.S. Pat. No. 3,130,204].

[0082] 6-Chloromethyl-3-hydroxy-pyran-4(1H)-one (chlorckojic acid)

[0083] The product was collected by filtration and washed with petroleumether and then recrystallised from water to give the pure title compound(42.5 g, 75.9%) as colourless needles. m.p. 166-168° C. [lit. 166-167°C.: Tilbrook G Thesis Kings College London.1995].

[0084] 3-Hydroxy-6-methyl-pyran-4(1H)-one (allomaltol)

[0085] Recrystallisation from isopropanol afforded 14.8 g (62.8%) ofanalytically pure allomaltol as colourless plates. m.p. 152-153° C.[lit. 152-153° C. Tibrooke G Thesis as above].

[0086] 2-Hydroxymethyl-3-hydroxy-pyran-4(1H)-one (α-hydroxymaltol)

[0087] Sodium hydroxide (4 g, 100 mmol, 1.25 eq.) dissolved in 10 mldistalled water was added to a solution of 3-hydroxy-pyran-4(l H)-one(8.96 g, 80 mmol, 1 eq.) in 50 ml methanol and allowed to stir at roomtemperature for 5minutes. 16 ml (200 mmol, 2.5 eq.) of 35% formaldehydesolution was added dropwise over 15 minutes and the solution was stirredovernight. After adjustment to pH 1 with 37% w/v hydrochloric acid, thereaction mixture was concentrated in vacuo to dryness and the resultingsolid was extracted with 2×100 ml of isopropanol at 90° C. Theisopropanol extracts were concentrated to yield the crude products.Recrystallisation from isopropanol afforded 9.7 g (85.4%) of the puretitle product as a white crystalline solid. m.p. 154-156° C. [lit.148-150° C. (Tate and Miller., 1964)]. ¹H-NMR (DMSO-d₆) δ: 4.4(s, 2H,2-CH₂OH), 4.6-5.7(br., 1H, 2-CH₂OH), 6.34(d, 1H, 5-H), 8.1 (d, 1H, 6-H),9.0(br., s, 1H, 3-OH)

[0088] 2-(1-Hydroxyethyl)-3-hydroxy-pyran-4(1H)-one

[0089] 3-Hydroxy-pyran-4(1H)-one (5.6 g, 50 mmol, 1 eq.) was added to 50ml water and the pH of the solution was adjusted to 10.5 using 50%aqueous sodium hydroxide. Acetaldehyde (2.64 g, 60 mmol, 1.25 eq.)dissolved in 20 ml water was slowly added dropwise over 1 hour and thesolution allowed to stir overnight. The reaction mixture was acidifiedto pH 1 with 37% w/v hydrochloric acid and concentrated in vacuo todryness. The residue was extracted with 2×70 ml of isopropanol at 90° C.The isopropanol extracts were combined and concentrated to yield afterrecrystallisation from toluene, the pure product (3.7 g, 47.4%) as apale yellow crystalline solid. m.p. 131-132° C. [lit. 130-131° C.(Ichimoto, 1970)]. ¹H-NMR (DMSO-d₆) δ: 1.3(d, 3H, 2-CHCH₃), 5.03(q, 1H,2-CHCH₃), 6.38(d, 1H, 5-H), 8.2(d, 1H, 6-H)

[0090] 2-Hydroxymethyl-3-hydroxy-6-methyl-pyran-4(1M)-one Allomaltol(12.6 g, 100 mmol, 1 eq.) was added to an aqueous solution containing4.4 g (110 mmol, 1.1 eq.) of sodium hydroxide in 100 ml distilled waterand stirred at room temperature for 5 minutes. 9 ml (110 mmol, 1.1 eq.)of 35% w/v formaldehyde solution was added dropwise over 10 minutes andthe solution allowed to stir overnight. Acidification to pH 1 usingconcentrated hydrochloric acid and cooling to 3-5° C. for 12 hours gavea crystalline deposit. The title product was isolated by filtration ascolourless needles (12.8 g, 82%). m.p. 159-161° C. [lit. (1): 157-158°C.; lit. (2): 161-163° C.]. Tilbrook (1993) Recrystallisation solventethanol. ¹H-NMR (DMSO-d₆) δ: 2.30 (s, 3H, 6-CH₃), 4.5(s, 2H, 2-CH₂OH),4.6-5.7(br, 1H, 2-CH₂OH), 6.25 (s, 1H, 5-H), 8.7-9.2 (br., 1H, 3-OH)

[0091] 2-(1-Hydroxyethyl)-3-hydroxy-6-methyl-pyran-4(1H)-one

[0092] Allomaltol (12.6 g, 100 mmol, 1 eq.) was added to 100 ml waterand the pH of the solution was adjusted to 10.5 using 50% aqueous sodiumhydroxides. Acetaldehyde (5.5 g, 125 mmol, 1.25 eq.) dissolved in 25 mlwater was slowly added dropwise over 1 hour and the solution allowed tostir overnight. After adjustment to pH 1 with 37% hydrochloric acid, thereaction mixture was extracted with 3×150 ml of dichloromethane. Thecombined organic extracts were dried over anhydrous sodium sulphate,filtered and concentrated to yield the crude product. Recrystallisationfrom toluene afforded the pure product (14.1 g, 83%) as white needles.m.p. 127-130° C. [lit. 126-128° C.]. Ellis (1993) ¹H-NMR (DMSO-d₆) δ:1.25 (d, 3H, 2-CHCH₃), 2.2 (s, 3H, 6-CH₃), 4.9 (q, 1H, 2-CHCH₃), 5.2(br., s, 1H, 2-CHOH), 6.1 (s, 1H, 5-H), 8.6 (br., s, 1H, 3-OH)

[0093] 2-(1-Hydroxypropyl)-3-hydroxy-6-methyl-pyran-4(1H)-one

[0094] Allomaltol (12.6 g, 100 mmol, 1 eq.) was added to 100 ml waterand the pH of the solution was adjusted to 10.5 using 50% aqueous sodiumhydroxides. Propionaldehyde (8.7 g, 150 mmol, 1.5 eq.) dissolved in 50ml methanol was slowly added dropwise over 1 hour and the solutionallowed to stir at room temperature for 48 hours. After adjustment to pH1 with 37% hydrochloric acid, the reaction mixture was evaporated todryness and the residue taken up into 300 ml of dichloromethane. Theorganic layer was washed with water (150 ml), dried over anhydroussodium sulphate, filtered and concentrated to yield the crude product.Recrystallisation from toluene afforded the pure product (14.5 g, 78.9%)as a white crystalline solid. m.p. 134-136° C. [lit. 132-135° C. Ellis(1993)]. ¹H-NMR (CDCl₃) δ: 1.12 (t, 3H, 2-CHCH₂CH₃), 1.7-2.3 (m, 2H,2-CHCH₂CH₃), 2.45 (s, 3H, 6-CH₃), 4.95 (q, 1H, 2-CHCH₂CH₃), 5.0-6.0(br., 1H, 2-CHOH), 6.3 (s, 1H, 5-H)

[0095] Novel Intermediates

EXAMPLE 1 8-Oxo-4,8-dihydro-2-phenyl-4H-pyrano[3,2-d]-m-dioxin

[0096] A solution of 2-hydroxymethyl-3-hydroxy-pyran-4(1H)-one (2.84 g,20 mmol, 1 eq.), benzaldehyde dimethyl acetal (6.08 g, 40 mmol, 2 eq.)and toluene-p-sulphonic acid monohydrate (0.04 g, cat.) in 50 ml DMF wasrotated under aspirator pressure at 80° C. for 3 hours. The solvent wasremoved under high vacuum, the residue taken up into 100 mldichloromethane. The organic solution was washed successively withaqueous Na₂CO₃ and brine. After drying over magnesium sulphate, thesolvent was removed to give the crude product. Recrystallisation fromCH₂Cl_(2/)Pet. ether 40/60 afforded the pure title compound (3.77 g,82%) as a white crystalline solid. m.p. 141-143° C. ¹H-NMR (CDCl₃) δ:4.72 (d, 2H, CH₂O), 5.88 (s, 1H, CHPh), 6.35 (d, 1H, 7-H(pyranone)),7.2-7.9 (m, 6H, Ar & 6-H(pyranone)) Anal. Calcd. for C₁₃H₁₀O₄: C, 67.82;H, 4.38%. Found: C, 68.13; H, 4.26%

EXAMPLE 2 8-Oxo-4,8-dihydro-4-methyl-2-phenyl-4H-pyrano[3,2-d]-m-dioxin

[0097] In an analogous procedure in the preparation of8-oxo-4,8-dihydro-2-phenyl-4H-pyrano[3,2-d]-m-dioxin using2-(1-hydroxyethyl)-3-hydroxy-pyran-4(1H)-one yielded the crude product.Purification by column chromatography on silica gel (eluant: EtOAc)furnished the title compound after recrystallisation from EtOAc/Pet.ether 40/60,as a white crystalline solid (yield=84.5%). m.p. 112-113° C.¹H-NMR (CDCl₃) δ: 0.55 (d, 3H, CHCH₃), 5.0 (q, 1H, CHCH₃), 5.8 (s, 1H,CHPh), 6.25 (d, 1H, 7-H(pyranone)), 7.1-7.75 (m, 6H, Ar & 6-H(pyranone))Anal. Calcd. for C₁₄H₁₂O₄: C, 68.85; H, 4.95%. Found: C, 68.63; H,4.86%.

EXAMPLE 3 8-Oxo-4,8-dihydro-6-methyl-2-phenyl-4H-pyrano[3,2-d]-m-dioxin

[0098] In an analogous procedure in the preparation of8-oxo-4,8-dihydro-2-phenyl-4H-pyrano [3,2-d3-m-dioxin using²-hydroxymethyl-3-hydroxy-6-methyl-pyran-4(1H)-one afforded the titlecompound (Yield=82.1%) after recrystallisation from EtOAc/Pet. ether40/60,as a white crystalline solid; m.p. 91-94° C. ¹H-NMR (CDCl₃) δ:2.25 (s, 3H, 6-CH₃), 4.75 (d, 2H, CH₂O), 5.9 (s, 1H, CHPh), 6.18 (s, 1H,7-H(pyranone)), 7.2-7.8 (m, 5H, Ar) Anal. Calcd. for C₁₄H₁₂O₄: C, 68.85;H, 4.95%. Found: C, 68.63; H, 4.86%

EXAMPLE 48-Oxo-4,8-dihydro-4,6-dimethyl-2-phenyl-4H-pyrano[3,2-d]-m-dioxin

[0099] In an analogous procedure in the preparation of8-oxo-4,8-dihydro-2-phenyl-4H-pyrano[3,2-d]-m-dioxin using2-(1-hydroxyethyl)-3-hydroxy-6-methyl-pyran-4 (1H )-one yielded thecrude product. Purification by column chromatography on silica gel(eluant: EtOAc) furnished the title compound after recrystallisationfrom EtOAc/Pet. ether 40/60,as a white crystalline solid (yield 86.7%).m.p. 120-122° C. ¹H-NMR (CDCl₃) δ: 1.6 (d, 3H, CHCH₃), 2.25 (s, 3H,6-CH₃), 5.08 (q, 1H, CHCH₃), 5.9 (s, 1H, CHPh), 6.18 (s, 1H,7-H(pyranone)), 7.2-7.8 (m, 5H, Ar) Anal. Calcd. for C₁₅H₁₄O₄: C, 69.76;H, 5.46%. Found: C, 69.94; H, 5.67%.

EXAMPLE 58-Oxo-4,8-dihydro-4-ethyl-6-methyl-2-phenyl-4H-pyrano[3,2-d]-m-dioxin

[0100] In an analogous procedure in the preparation of8-oxo-4,8-dihydro-2-phenyl-4H-pyrano [3,2-d]-m-dioxin using2-(1-hydroxyproyl)-3-hydroxy-6-methyl-pyran-4 (1H)-one afforded thetitle compound after recrystallisation from EtOAc/Pet. ether 40/60,as awhite, crystalline solid (Yield=61.3%); m.p. 111-114° C. ¹H-NMR (CDCl₃)δ: 1.0 (t, 3H, CHCH₂CH₃), 1.6-2.1 (m, 2H, CHCH₂CH₃), 2.2 (s, 3H, 6-CH₃),4.7-5.0 (m, 1H, CHCH₂CH₃), 5.8 (s, 1H, CHPh), 6.1 (s, 1H,7-H(pyranone)), 7.15-7.7 (m, 5H, Ar) Anal. Calcd. for C₁₆H₁₆O₄: C,70.58; H, 4.92%. Found: C, 70.35; H, 4.89%

[0101] 2-Hydroxymethyl-3-benzyloxy-6-methyl-pyran-4 (1H)-one (known).

[0102] Sodium hydroxide (4.84 g, 121 mmol, 1.1 eq.) dissolved in 10 mldistilled water was added to 100 ml methanol containing2-hydroxymethyl-3-hydroxy-6-methyl-pyran-4 (1H)-one (17.2 g, 110 mmol, 1eq.) and heated to reflux. Benzyl bromide (20.7 g, 121 mmol, 1 eq.) wasadded dropwise over 30 minutes and then refluxed overnight The reactionmixture was concentrated in vacuo, the residue taken up into 300 mldichloromethane and the inorganic salts filtered off. Thedichloromethane layer was washed with 2×100 ml 5% w/v sodium hydroxidesolution, 100 ml water, dried (Na₂SO₄), and concentrated in vacuo toyield the crude product as a yellow crystalline solid. Recrystallisationfrom CH₂Cl₂/Pet. ether 40/60afforded the title product in 80% yield(21.6 g) as a white crystalline solid. m.p. 115-116° C. [lit. 114-116°C. Tilbrook (1995)]. ¹H-NMR (CDCl₃) δ: 2.2 (s, 3H, 6-CH₃), 2.6 (br., s,1H, 2-CH₂OH), 4.3 (br., s, 2H, 2-CH₂OH), 5.18 (s, 2H, CH₂Ph), 6.16 (s,1H, 5-H(pyranone)), 7.4 (s, 5H, Ar)

NOVEL INTERMEDIATES AND ORALLY ACTIVE PRODRUGS OF THE INVENTION EXAMPLE6 2-(1-Hydroxyethyl)-3-benzyloxy-6-methyl-pyran-4 (1H-one

[0103] The title compound was prepared by the method outlined for2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one, using 8.5 g (50mmol, 1 eq.) of 2-hydroxyethyl)-3-hydroxy-6-methyl-pyran-4 (1H)-one and9.5 g benzyl bromide (55 mmol, 1.1 eq.) to yield the pure product 10.1 g(77.7%) after recrystallisation from CH₂Cl₂/Pet. ether 40/60,as a whitecrystalline solid. m.p 91-92° C. ¹H-NMR (CDCl₃) δ: 1.25 (d, 3H,2-CHCH₃), 2.25 (s, 3H, 6-CH₃), 2.55 (br., s, 1H, 2-CHOH), 4.9 (q, 1H,2-CHCH₃), 5.18 (s, 2H, CH₂Ph), 6.16 (s, 1H, 5-H (pyranone)), 7.4 (s, 5H,Ar)

EXAMPLE 7 2-(1′-Hydroxypropyl)-3-benzyloxy-6-methyl-pyran-4 (1H)-one

[0104] The title compound was prepared by the method outlined for2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one, using 7.36 g (40mmol, 1 eq.) of 2-(1-hydroxypropyl)-3-hydroxy-6-methyl-pyran-4(1H)-oneand 7.5 g benzyl bromide (44 mmol, 1.1 eq.) to yield the pure product8.9 g (81.2%) after recrystallisation from CH₂Cl₂/Pet. ether 40/60, as awhite crystalline solid. m.p. 88-89° C. ¹H-NMR (CDCl₃) δ: 0.8 (t, 3H,2-CHCH₂CH₃), 1.2-1.9 (m, 2H, 2-CHCH₂CH₃), 2.2 (s, 3H, 6-CH₃), 2.4 (br.,s, 1H, 2-CHOH), 4.5 (t, 1H, 2-CHCH₂CH₃), 5.08 (s, 2H, CH₂Ph), 6.04 (s,1H, 5-H(pyranone)), 7.28 (s, 5H, Ar)

[0105] 2-Hydroxymethyl-3-benzyloxy-pyran-4 (1H)-one (known).

[0106] The title compound was prepared by the method outlined for2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4 (1H)-one, using 7.1 g (50mmol, 1 eq.) of 2-hydroxymethyl-3-hydroxy-pyran-4 (1H)-one and 9.5 gbenzyl bromide (55 mmol, 1.1 eq.) to yield the crude product as anorgane oil. Further purification by column chromatography on silica gel(eluant: 10% CH₃OH/90% CHCl₃) furnished the pure product (9.4 g, 81%) asa bright yellow oil. (Looker and Clifton (1986). ¹H-NMR (CDCl₃) δ: 1.8(br., s, 1H, 2-CH₂OH), 4.4 (br., s, 2H, 2-CH₂OH), 5.18 (s, 2H, CH₂Ph),6.35 (d, 1H, 5-H(pyranone)), 7.4 (s, 5H, Ar), 7.65 (d, 1H,6-H(pyranone))

EXAMPLE 8 2-(1′-Hydroxyethyl)-3-benzyloxy-pyran-4(1H)-one

[0107] The title compound was prepared by the method outlined for2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one, using 4.68 g (30mmol, 1 eq.) of 2-(1-hydroxyethyl)-3-hydroxy-pyran-4(1H)-one and 5.64 gbenzyl bromide (33 mmol, 1.1 eq.) to yield the pure product 6.1 g (82%)after recrystallisation from CH₂Cl₂/Pet. ether 40/60,as a whitecrystalline solid. m.p. 97-100° C. ¹H-NMR (CDCl₃) δ3: 1.35 (d, 3H,2-CHCH₃), 2.5 (br., s, 1H, 2-CHOH), 4.95 (q, 1H, 2-CHCH₃), 5.21 (s, 2H,CH₂Ph), 6.38 (d, 1H, 5-H(pyranone)), 7.4 (s, 5H, Ar), 7.7 (d, 1H,6-H(pyranone))

ORALLY ACTIVE PRODRUGS OF THE INVENTION EXAMPLE 92-Methoxymethyl-3-benzyloxy-6-methyl-pyran-4 (1H)-one

[0108] To a suspension of sodium hydride (0.48 g, 20 mmol, 2 eq.) in 30ml dry DMF was added2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (2.46 g, 10 mmol, 1eq.) followed by dropwise addition of iodomethane (4.26 g, 30 mmol, 3eq.) at 0° C. under nitrogen. After stirring for 30 minutes at thistemperature, the reaction mixture was poured into ice cold water (100ml) and extracted with dichloromethane (3×50 ml). The combined organicfractions were dried over anhydrous sodium sulphate, filtered andconcentrated in vacuo to yield the crude product (2.6 g, 100%) as anorange oil which solidified on cooling. Recrystallisation fromCH₂Cl_(2/)Pet. ether 40/60afforded the pure product (2.35 g, 90%) as awhite crystalline solid. m.p. 30-32° C. ¹H-NMR (CDCl₃) δ: 2.25 (s, 3H,6-CH₃), 3.26 (s, 3H, OCH₃), 4.2 (s, 2H, 2-CH₂OCH₃), 5.18 (s, 2H, CH₂Ph),6.16 (s, 1H, 5-H(pyranone)), 7.35 (s, 5H, Ar)

EXAMPLE 10 2-(1-Methoxyethyl)-3-benzyloxy-6-methyl-pyran-4 (1H)-one

[0109] In an analogous procedure in the preparation of2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one using2-(1-hydroxyethyl)-3-benzyloxy-6-methyl-pyran-4 (1H)-one (2.6 g, 10mmol, 1 eq.) yielded the title compound as an orange oil (2.65 g, 97%).Further purification by column chromatography on silica gel (eluant:EtOAc) furnished the pure product as a bright yellow oil. ¹H-NMR (CDCl₃)δ: 1.18 (d, 3H, 2-CHCH₃), 2.25 (s, 3H, 6-CH₃), 3.1 (s, 3H OCH₃), 4.5 (q,1H, 2-CHCH₃), 5.2 (s, 2H, CH₂Ph), 6.16 (s, 1H, 5-H(pyranone)), 7.4 (s,5H, Ar).

EXAMPLE 11 2-(1′-Methoxypropyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one

[0110] In an analogous procedure in the preparation of2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one using2-(1-hydroxypropyl)-3-benzyloxy-6-methyl-pyran-4 (1H)-one (5.48 g, 20mmol, 1 eq.) yielded the title compound (5.2 g, 90.3%) as an orange oilwhich solidified on cooling. Recrystallisation from CH₂Cl₂/Pet. ether40/60afforded the pure product as a white crystalline solid. m.p. 63-65°C. ¹H-NMR (CDCl₃) δ: 0.9 (t, 3H, 2-CHCH₂CH₃), 1.2-1.8 (m, 2H,2-CHCH₂CH₃), 2.34 (s, 3H, 6-CH₃), 3.18 (s, 3H OCH₃), 4.3 (t, 1H,2-CHCH₂CH₃), 5.24 (s, 2H, CH₂Ph), 6.2 (s, 1H, 5-H(pyranone)), 7.38 (s,5H, Ar)

EXAMPLE 12 2-Methoxymethyl-3-benzyloxy-pyran-4(1H)-one

[0111] In an analogous procedure in the preparation of2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4 (1H)-one using2-hydroxymethyl-3-benzyloxy-pyran-4(1H)-one (2.32 g, 10 mmol, 1 eq.)yielded the title compound as an orange oil (2.5 g, ˜100%). Furtherpurification by column chromatography on silica gel (eluant: EtOAc)furnished the pure product as a bright yellow oil. ¹H-NMR (CDCl₃) δ:3.25 (s, 3H, OCH₃), 4.3 (s, 2H, 2-CH₂OCH₃), 5.2 (s, 2H, CH₂Ph), 6.3 (d,1H, 5-H(pyranone)), 7.3 (s, 5H, Ar), 7.65 (d, 1H, 6-H (pyranone))

EXAMPLE 13 2-(1-Methoxyethyl)-3-benzyloxy-pyran-4(1H)-one

[0112] In an analogous procedure in the preparation of2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one using2-(1-hydroxyethyl)-3-benzyloxy-pyran-4(1H)-one (2.46 g, 10 mmol, 1 eq.)yielded the title compound as a yellow oil (2.4 g, 92.3%). Furtherpurification by column chromatography on silica gel (eluant: EtOAc)furnished the pure product (2.1 g, 80.8%) as a bright yellow oil.¹H-NMR(CDCl₃) δ: 1.18 (d, 3H, 2-CHCH₃), 3.1 (s, 3H, OCH₃), 4.45 (q, 1H,2-CHCH₃), 5.2 (s, 2H, CH₂Ph), 6.3 (d, 1H, 5-H(pyranone)), 7.3 (s, 5H,Ar), 7.65 (d, 1H, 6-H(pyranone))

EXAMPLE 14 2-(1-Ethoxyethyl)-3-benzyloxy-6-methyl-pyran-4 (1H)-one

[0113] In an analogous procedure in the preparation of2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one using2-(1-hydroxyethyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one (5.2 g, 20 mmol,1 eq.) and 9.36 g iodoethane (60 mmol, 3 eq.) yielded the title compoundas an orange oil (5.4 g, 94% Crude). Further purification by columnchromatography on silica gel (eluant: EtOAc) furnished the pure productas a bright yellow oil. ¹H-NMR (CDCl₃) δ: 1.05-1.65 (m, 6H, 2-CHCH₃&OCH₂CH₃), 2.38 (s, 3H, 6-CH₃), 3.3 (q, 2H, OCH₂CH₃), 4.65 (q, 1H,2-CHCH₃), 5.25 (s, 2H, CH₂Ph), 6.2 (s, 1H, 5-H(pyranone)), 7.4 (s, 5H,Ar)

NOVEL INTERMEDIATES OF THE INVENTION EXAMPLE 158-Oxo-4,8-dihydro-2-phenyl-5-methyl-4H-pyridino[3,2-d]-m-dioxin

[0114] To a solution of8-oxo-4,8-dihydro-2-phenyl-4H-pyrano[3,2-d]-m-dioxin (2.3 g, 10 mmol, 1eq.) in ethanol (10 ml)/water (10 ml) was added 2.5 ml (20 mmol, 2 eq.)of 40% aqueous methylamine followed by 2N sodium hydroxide solutionuntil pH 12.5 was obtained. The reaction mixture was sealed in athick-walled glass tube and stirred at 70° C. for 3 hours. Afteradjustment to pH 1 with concentrated hydrochloric acid, the solvent wasremoved by rotary evaporation prior to addition of water (50 ml) andwashing with diethyl ether (3×50 ml). Subsequent adjustment of theaqueous fraction to pH 7 with ION sodium hydroxide solution was followedby extraction into dichloromethane (4×50 ml), the combined organiclayers then being dried over anhydrous sodium sulphate, filtered, rotaryevaporated to give a yellow solid. Recrystallisation frommethanol/diethyl ether afforded the pure product (1.6 g, 65.8%) as alight yellow crystalline solid. m.p. 210-21 1° C. ¹H-NMR (DMSO-d₆) δ:3.55 (s, 3H, N—CH₃), 5.08 (s, 2H, CH₂O), 5.92 (s, 1H, CHPh), 6.12 (d,1H, 7-H(pyridinone)), 7.25-7.85 (m, 6H, Ar & 6-H(pyridinone))

EXAMPLE 168-Oxo-4,8-dihydro-2-phenyl-5,6-dimethyl-4H-pyridino[3,2-d]-m-dioxin

[0115] In an analogous procedure in the preparation of8-oxo-4,8-dihydro-2-phenyl-5-methyl-4H-pyridino[3 ,2-d]-m-dioxin using8-oxo-4,8-dihydro-6-methyl-2-phenyl-4H-pyrano[3,24]-m-Dioxin (1.22 g, 5mmol) yielded the title compound as a white powder (0.85 g, 66%). m.p.256-258° C. ¹H-NMR (methanol-d₄) δ: 2.2 (s, 3H, 6-CH₃), 3.35 (s, 3H,N—CH₃), 4.95 (s, 2H, CH₂O), 5.8 (s, 1H, CHPh), 6.5 (s, 1H,7-H(pyridinone)), 7.0-7.5 (m, SH, Ar)

EXAMPLE 178-Oxo-4,8-dihydro-2-phenyl-4,5,6-trimethyl-4H-pyridino[3,2-d]-m-dioxin

[0116] In an analogous procedure in the preparation of8-oxo-4,8-dihydro-2-phenyl-5-methyl-4H-pyridino[3 ,2-d]-m-dioxin using8-oxo-4,8-dihydro-4,6-dimethyl-2-phenyl-4H-pyrano-[3,2-d]-m-dioxin (2.58g, 10 mmol) yielded the crude product. Further purification by columnchromatography on silica gel (eluant: 20% CH₃OH/80% CHC₃) afforded thepure, title compound (1.54 g, 56.8%) after recrystallisation frommethanol diethyl ether as a pale yellow crystalline solid. m.p. 199-201°C. ¹H-NMR (DMSO-d₆) 8: 1.7 (dd, 3H, CHCH₃), 2.35 (s, 3H, 6-CH₃), [3.44(s, isomer B) & 3.5 (s, isomer A); 3H, N—CH₃], 4.9-5.4 (m, 1H, CHCH₃),(5.75 (s, isomer A) & 6.05 (s, isomer B); 1H, CHPh], 6.35 (s, 1H,7-H(pyridinone)), 7.2-7.9 (m, 5H, Ar)

EXAMPLE 188-Oxo-4,8-dihydro-2-phenyl-4-ethyl-5,6-dimethyl-4H-pyridino[3,2-d]-m-dioxin

[0117] In an analogous procedure in the preparation of8oxo-4,8-dihydro-2-phenyl-5-methyl-4H-pyridino[3,2-d]-m-dioxin using8-oxo-4,8-dihydro-4ethyl-6-methyl-2-phenyl-4H-pyrano-[3,2-d]-m-dioxin(4.08 g, 15 mmol) yielded the crude product. Further purification bycolumn chromatography on silica gel (eluant: 20% CH₃OH/80% CHCl₃)afforded the pure title compound (1.7 g, 39.8%) after recrystallisationfrom CHCl₃/diethyl ether as a pale yellow crystalline solid. m.p.185-187° C. ¹H-NMR (DMSO-d₆) δ: 0.8-1.4 (m, 3H, CHCH₂CH₃), 1.5-2.2 (m,2H, CHCH₂CH₃), 2.3 (s, 3H, 6-CH₃), δ 3.38 (s, isomer B) & 3.45 (s,isomer A); 3H, N—CH₃, [4.5-4.8 (m, isomer B) & 4.9-5.4 (m, isomer A);1H, CHCH₂CH₃], [5.68 (s, isomer A) & 5.95 (s, isomer B); 1H, CHPh], 6.25(s, 1H, 7-H (pyridinone)), 7.2-7.8 (m, 5H, Ar)

EXAMPLE 19 8-Oxo-4,8-dihydro-2-phenyl-4-methyl-5-ethyl-4H-pyridino[3,2-d]-m-dioxin

[0118] To a solution of8-oxo-4,8-dihydro-4-methyl-2-phenyl-4H-pyrano[3,2-d]-m-dioxin (1.7 g, 7mmol, 1 eq.) in ethanol (10 ml)/water (10 ml) was added 1.2 ml (14 mmol,2 eq.) of 70% aqueous ethylamine followed by 2N sodium hydroxidesolution until pH 12.5 was obtained. The reaction mixture was sealed ina thick-walled glass tube and stirred at 70° C. for 3 hours. Afterremoval the solvent, the residue was purified by column chromatographyon silica gel (eluant: 15% CH₃OH/85% CHCl₃) to afford the title product(1.5 g, 79.1%) as a yellow oil. ¹H-NMR (CDCl₃) δ: 1.2-2.2 (m, 6H, CHCH₃&N—CH₂CH₃), 3.4-4.0 (m, 2H, N—CH₂CH₃), 4.8-5.4 (m, 1H, CHCH₃), [5.6 (s,isomer A) & 6.0 (s, isomer B); 1H, CHPh], 6.3 (d, 1H, 7-H(pyridinone)),7.0-7.7 (m, 6H, Ar & 6-H(pyridinone)).

EXAMPLE 208-Oxo-4,8-dihydro-2-phenyl-5-(3-hydroxypropyl)4H-pyridino[3,2-d]-m-dioxin

[0119] To a solution of8-oxo-4,8-dihydro-2-phenyl-4H-pyrano[3,2-d]-m-dioxin (3.45 g, 15 mmol, 1eq.) in ethanol (50 ml)/water (50 ml) was added 3-hydroxypropylamine(2.25 g, 30 mmol, 2 eq.) followed by 2N sodium hydroxide solution untilpH 12.5 was obtained. The reaction mixture was refluxed for 3 hours. TLCanalysis (10% CH₃OH/90% CHCl₃) showed that no starting material waspresent. After removal of solvent by rotary evaporation, the residue waspurified by column chromatography on silica gel (eluant: 20% CH₃OH/80%CHCl₃) to afford the title compound (3.35 g, 77.8%) as a yellowcrystalline solid m.p. 73-76° C. ¹H-NMR (CDCl₃) δ: 1.5-2.1 (m, 2H,N—CH₂CH₂CH₂O), 3.2-4.0 (m, 4H, N—CH₂CH₂CH₂O), 4.0-5.2 (br., 1H, OH), 4.8(s, 2H, CH₂O), 5.7 (s, 1H, CHPh), 6.2 (d, 1H, 7-H(pyridinone)), 7.0-7.8(m, 6H, Ar & 6-H(pyridinone))

EXAMPLE 218-Oxo-4,8-dihydro-2-phenyl-4-methyl-5-(3-hydroxypropyl)4H-pyridino[3,2-d]-m-dioxin

[0120] In an analogous procedure in the preparation of8-oxo-4,8-dihydro-2-phenyl-5-(3-hydroxypropyl)-4H-pyridino[3,2-d]-m-dioxinusing 8-oxo-4,8-dihydro-4-methyl-2-phenyl-4H-pyrano[3,2-d]-m-dioxin(1.83 g, 7.5 mmol, 1 eq.) yielded the title compound (1.3 g, 57.6%)after purification by column chromatography on silica gel (eluant: 20%CH₃OH/80% CHCl₃) as a yellow oil. ¹H-NMR (CDCl₃) δ: 1.5 (d, 3H, CHCH₃),1.5-2.1 (m, 2H, N—CH₂CH₂CH₂O), 3.2-4.0 (m, 4H, N—CH₂CH₂CH₂O), 4.0-5.2(br., 1H, OH), 5.28 (q, 1H, CHCH₃), 5.58 (s, 1H, CHPh), 6.2 (d, 1H,7-H(pyridinone)), 7.0-7.8 (m, 6H, Ar & 6-H (pyridinone))

EXAMPLE 228-Oxo-4,8-dihydro-2-phenyl-5-[(3-benzoyloxy)propyl]-4H-pyridino[3,2-d]-m-dioxin

[0121] A solution of triphenyl phosphine (3.46 g, 13.2 mmol, 1.1 eq.)and8-oxo-4,8-dihydro-2-phenyl-5-(3-hydroxypropyl)-4H-pyridino[3,2-d]-m-dioxin(3.3 g, 12 mmol, 1 eq.) in dry tetrahydrofuran (100 ml) was addeddropwise to a solution of diethyl azodicarboxylate (2.3 g, 13.2 mmol,1.1 eq.) and benzoic acid (1.5 g, 12 mmol, 1 eq.) in dry tetrahydrofuran(30 ml) at room temperature. After stirring the mixture overnight atroom temperature, the solvent was removed under reduced pressure. Theresidue thus obtained was purified by column chromatography on silicagel (eluant: 12% CH₃OH/88% CHCl₃) to afford the title compound (4.1 g,89.7%) as a light yellow oil. ¹H-NMR (CDCl₃) δ: 1.95-2.55 (m, 2H,N—CH₂CH₂CH₂O), 3.82 (t, 2H, N—CH₂CH₂CH₂O), 4.34 (t, 2H, N—CH₂CH₂CH₂O),4.9 (s, 2H, CH₂O), 5.8 (s, 1H, CHPh), 6.3 (d, 1H, 7-H(pyridinone)),7.0-8.2 (m, 1H, Ar & 6-H (pyridinone)).

ORALLY ACTIVE PRODRUGS OF THE INVENTION EXAMPLE 231,6-Dimethyl-2-methoxymethyl-3-benzyloxy-pyridin-4 (1H)-onehydrochloride

[0122] To a solution of 2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4 (IH)-one (3.12 g, 12 mmol, 1 eq.) in ethanol (10 ml)/water (10 ml) wasadded 2.8 g (36 mmol, 3 eq.) of 40% aqueous methylamine followed by 2Nsodium hydroxide solution until pH 13was obtained. The reaction mixturewas sealed in a thick-walled glass tube and stirred at 70° C. for 12hours. After adjustment to pH 1 with concentrated hydrochloric acid, thesolvent was removed by rotary evaporation prior to addition of water (50ml) and washing with diethyl ether (3×50 ml). Subsequent adjustment ofthe aqueous fraction to pH 7 with 1ON sodium hydroxide solution wasfollowed by extraction into dichloromethane (4×50 ml), the combinedorganic layers then being dried over anhydrous sodium sulphate, filteredand the solvent removed in vacuo. The residue was redissolved in 30 mlmethanol and adjusted to pH 1 with concentrated hydrochloric acid. Thesolution was reconcentrated in vacuo to yield the crude product.Recrystallization from methano/diethyl ether gave the pure titlecompound (3.05 g, 82%) as a white crystalline solid m.p. 125-128° C.¹H-NMR (DMSO-d₆) δ: 2.6 (s, 3H, 6-CH₃), 3.26 (s, 3H, OCH₃), 3.86 (s, 3H,N—CH₃), 4.6 (s, 2H, 2-CH₂OCH₃), 5.04 (s, 2H, CH₂Ph), 5.5-6.5 (br., 1H,OH), 7.2-7.8 (m, 6H, Ar & 5-H(pyridinone))

EXAMPLE 24 1,6-Dimethyl-2-(1-methoxyethyl)-3-benzyloxy-pyridin-4(1H)-one hydrochloride

[0123] The title compound was prepared by the method outlined for1,6-dimethyl-2-methoxy-methyl-3-benzyloxy-pyridin-4 (1H)-onehydrochloride, using 3.56 g (13 mmol, 1 eq.) of2-(1-methoxyethyl)-3-benzyloxy-6-methyl-pyran-4 (1H)-one to yield thepure product 2.64 g (62.8%) after recrystallisation frommethanol/diethyl ether, as a white crystalline solid m.p. 117-119° C.¹H-NMR (DMSO-d₆) 3: 1.3 (d, 3H, CHCH₃), 2.54 (s, 3H, 6-CH₃), 3.04 (s,3H, OCH₃), 3.96 (s, 3H, N—CH₃), 5.08 (s, 2H, CH₂Ph), 5.12 (q, 1H,CHCH₃), 7.4 (s, 5H, Ar), 7.6 (s, 1H, 5-H(pyridinone))

EXAMPLE 25 1-Ethyl-2-methoxymethyl-3-benzyloxy-6-methyl-pyridin-4(1H)-one hydrochloride

[0124] The title compound was prepared by the method outlined for1,6-dimethyl-2-methoxy-methyl-3-benzyloxy-pyridin-4 (1H)-onehydrochloride, using 6.5 g (25 mmol, 1 eq.) of2-(1-methoxymethyl)-3-benzyloxy-6-methyl-pyran-4 (1H)-one and 4.82 g (75mmol, 3 eq.) of 70% aqueous ethylamine to yield the pure product 3.7 g(45.7%) after recrystallisation from methanol/diethyl ether, as a whitecrystalline solid m.p. 114-116° C. ¹H-NMR (DMSO-d₆) δ: 1.3 (t, 3H,N—CH₂CH₃), 2.64 (s, 3H, 6-CH₃), 3.27 (s, 3H, OCH₃), 4.35 (q, 2H,N—CH₂CH₃), 4.6 (s, 2H, 2-CH₂OCH₃), 5.1 (s, 2H, CH₂Ph), 6.0-7.0 (br., 1H,OH), 7.45 (s, 5H, Ar), 7.52 (s, 1H, 5-H(pyridinone))

EXAMPLE 26 1-Ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4 (1H)-one

[0125] To a solution of 2-methoxymethyl-3-benzyloxy-pyran-4 (1H)-one(2.46 g, 10 mmol, 1 eq.) in ethanol (10 ml)/water (10 ml) was added 1.93g (30 mmol, 3 eq.) of 70% aqueous ethylamine followed by 2N sodiumhydroxide solution until pH 13was obtained. The reaction mixture wassealed in a thick-walled glass tube and stirred at 70° C. overnight.After adjustment to pH I with concentrated hydrochloric acid, thesolvent was removed by rotary evaporation prior to addition of water (50ml) and washing with diethyl ether (3×50 ml). Subsequent adjustment ofthe aqueous fraction to pH 7 with ION sodium hydroxide solution wasfollowed by extraction into dichloromethane (4×50 ml), the combinedorganic layers then being dried over anhydrous sodium sulphate, filteredand the solvent removed in vacuo. The residue was purified by columnchromatography on silica gel (eluant: 15% CH₃OH/85% CHCl₃) to afford thetitle compound (2.05 g, 75.1%) as a yellow oil. ¹H-NMR (CDCl₃) δ: 1.3(t, 3H, N—CH₂CH₃), 3.24 (s, 3H, OCH₃), 3.95 (q, 2H, N—CH₂CH₃), 4.35 (s,2H, 2-CH₂OCH₃), 5.25 (s, 2H, CH₂Ph), 6.45 (d, 1H, 5-H (pyridinone)),7.15-7.6 (m, 6H, Ar & 5-H(pyridinone)).

EXAMPLE 27 1-Ethyl-2-(1-methoxyethyl)-3-benzyloxy-pyridin-4 (1H)-one

[0126] In an analogous procedure in the preparation of1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4 (1H)-one using2-(1-methoxyethyl)-3-benzyloxy-pyran-4(1H)-one 3.12 g (12 mmol, 1 eq.)yielded the title compound (1.03 g, 29.6%) after purification by columnchromatography on silica gel (eluant: 15% CH₃OH/85% CHCl₃) as a yellowoil. ¹H-NMR (CDCl₃) δ: 1.1-1.6 (m, 6H, CHCH₃& N—CH₂CH₃), 3.0 (s, 3H,OCH₃), 4.1 (q, 2H, N—CH₂CH₃), 4.95 (q, 1H, CHCH₃), 5.18 (s, 2H, CH₂Ph),6.3 (d, 1H, 5-H (pyridinone)), 7.0-7.5 (m, 6H, Ar & 5-H(pyridinone))

EXAMPLE 28 1,6-Dimethyl-2-(1-methoxypropyl)-3-benzyloxy-pyridin-4(1H)-one

[0127] In an analogous procedure in the preparation of1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4 (1H)-one using2-(1-methoxypropyl)-3-benzyloxy-6-methyl-pyran-4 (1H)-one 4.32 g (15mmol, 1 eq.) and 3.49 g (45 mmol, 3 eq.) of 40% aqueous methylamineyielded the title compound (1.7 g, 37.6%) after purification by columnchromatography on silica gel (eluant: 15% CH₃OH/85% CHCl₃) as a yellowoil. ¹H-NMR (CDCl₃) δ: 0.9 (t, 3H, CHCH₂CH₃), 1.1-1.9 (m, 2H, CHCH₂CH₃),2.3 (s, 3H, 6-CH₃), 3.05 (s, 3H, OCH₃), 3.65 (s, 3H, N—CH₃), 4.65-5.0(m, 1H, CHCH₂CH₃), 5.24 (s, 2H, CH₂Ph), 6.3 (d, 1H, 5-H (pyridinone)),7.1-7.6 (m, 6H, Ar)

EXAMPLE 29 1,6-Dimethyl-2-(1-ethoxymethyl)-3-benzyloxy-pyridin-4(1H)-one

[0128] In an analogous procedure in the preparation of1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4 (1H)-one using2-(1-ethoxymethyl)-3-benzyloxy-6-methyl-pyran-4 (1H)-one 5.76 g (20mmol, 1 eq.) and 4.65 g (60 mmol, 3 eq.) of 40% aqueous methylamineyielded the title compound (3.68 g, 61.1%) after purification by columnchromatography on silica. gel (eluant: 15% CH₃OH/85% CHCl₃) as a yellowoil. ¹H-NMR (CDCl₃) δ: 1.1-1.6 (m, 6H, CHCH₃& OCH₂CH₃), 2.3 (s, 3H,6-CH₃), 3.2 (q, 2H, OCH₂CH₃), 3.7 (s, 3H, N—CH₃), 5.2 (q, 1H, CHCH₃),5.25 (s, 2H, CH₂Ph), 6.3 (s, 1H, 5-H(pyridinone)), 7.1-7.6 (m, 5H, Ar)

DE-ALKYLATED ACTIVE METABOLITES OF ORALLY ACTIVE COMPOUNDS OF THEINVENTION EXAMPLE 30 1-Methyl-2-hydroxymethyl-3-hydroxy-pyridin-4(1H)-one hydrochloride

[0129] 8-Oxo-4,8-dihydro-2-phenyl-5-methyl-4H-pyridino[3,2-d]-m-dioxin(1.22 g, 5 mmol) was dissolved in 30 ml of ethanol and adjusted to pH 1with concentrated hydrochloric acid prior to hydrogenolysis for 12 hoursin the presence of 5% Pd/C catalyst (0.2 g). Filtration followed byrotary evaporation gave the crude product as a white solid.Recrystallization from methanol/diethyl ether gave the pure titlecompound (0.82 g, 86%) as a white crystalline solid. m.p. 157-159° C.¹H-NMR (DMSO-d₆) δ: 4.18 (s, 3H, N—CH₃), 4.8 (s, 2H, 2-CH₂OH), 7.4 (d,1H, 5-H(pyridinone)), 8.3 (d, 1H, 6-H(pyridinone)), 7.6-9.3 (br., 3H,OH) 10- Anal. Calcd. for C₇H₁₀NO₃Cl: C, 43.88; H, 5.26; N, 7.31%. Found:C, 44.14; H, 5.34; N, 7.28%

EXAMPLE 31 1,6-Dimethyl-2-hydroxymethyl-3-hydroxy-pyridin-4 (1H)-onehydrochloride

[0130] In an analogous hydrogenation procedure in the preparation of1-methyl-2-hydroxymethyl-3-hydroxy-pyridin-4 (1H)-one hydrochloride,using8-oxo-4,8-dihydro-2-phenyl-5,6-dimethyl-4H-pyridino[3,2-d]-m-dioxin(0.64 g, 2.5 mmol) and 5% Pd/C catalyst (0.1 g) yield the title compound0.45 g (87.5%) after recrystallisation from methanol/diethyl ether, as awhite crystalline solid. m.p. 140-143° C. ¹H-NMR (DMSO-d₆) δ: 2.7 (s,3H, 6-CH₃), 4.06 (s, 3H, N—CH₃), 4.86 (s, 2H, 2-CH₂OH), 7.4 (s, 1H,5-H(pyridinone)), 6.4-8.7 (br., 3H, OH) Anal. Calcd. forC₈H₁₂NO₃Cl⁻¹/₂H₂O: C, 44.77; H, 6.10; N, 6.53%. Found: C, 44.72; H,6.00; N, 6.26%

EXAMPLE 32 1,6-Dimethyl-2-(1-hydroxyethyl)-3-hydroxy-pyridin-4 (1H)-onehydrochloride

[0131] In an analogous hydrogenation procedure in the preparation of1-methyl-2-hydroxymethyl-3-hydroxy-pyridin-4 (1H)-one hydrochloride,using8-oxo-4,8-dihydro-2-phenyl-4,5,6-trimethyl-4H-pyridino[3,2-d]-m-dioxin(1.36 g, 5 mmol) and 5% Pd/C catalyst (0.3 g) yield the title compound0.9 g (82%) after recrystallisation from methanol/diethyl ether, as alight yellow crystalline solid. m.p. 208-212° C. ¹H-NMR (DMSO-d₆) δ: 1.4(d, 3H, CHCH₃), 2.5 (s, 3H, 6-CH₃), 4.04 (s, 3H, N—CH₃), 5.65 (q, 1H,CHCH₃), 7.3 (s, 1H, 5-H(pyridinone)), 7.5-10.0 (br., 3H, OH) Anal.Calcd. for C₉H₁₄NO₃Cl: C, 49.21; H, 6.42; N, 6.38%. Found: C, 49.12; H,6.33; N, 6.22%

EXAMPLE 33 1,6-Dimethyl-2-(1-hydroxypropyl)-3-hydroxy-pyridin-4(1H)-onehydrochloride

[0132] In an analogous hydrogenation procedure in the preparation of1-methyl-2-hydroxymethyl-3-hydroxy-pyridin-4 (1H)-one hydrochloride,using8-oxo-4,8-dihydro-2-phenyl-4-ethyl-5,6-dimethyl-4H-pyridino[3,2d]-m-dioxin(1.43 g, 5 mmol) and 5% Pd/C catalyst (0.3 g) yield the title compound0.93 g (79.7%) after recrystallisation from methanol/diethyl ether, as awhite crystalline solid. m.p. 221-223° C. ¹H-NMR (DMSO-d₆) δ: 0.8 (t,3H, CHCH₂CH₃), 1.3-2.1 (m, 2H, CHCH₂CH₃), 2.43 (s, 3H, 6-CH₃), 3.94 (s,3H, N—CH₃), 5.3 (t, 1H, CHCH₂CH₃), 7.15 (s, 1H, 5-H(pyridinone)),7.5-10.5 (br., 3H, OH) Anal. Calcd. for C₁₀H₁₆NO₃Cl: C, 51.40; H, 6.90;N, 5.99%. Found: C, 51.45; H, 6.82; N, 5.89%.

EXAMPLE 34 1-Ethyl-2-(1-hydroxyethyl)-3-hydroxy-pyridin-4 (1H)-onehydrochloride

[0133] In an analogous hydrogenation procedure in the preparation of1-methyl-2-hydroxymethyl-3-hydroxy-pyridin-4 (1H)-one hydrochloride,using8-oxo-4,8-dihydro-2-phenyl-4-methyl-5-ethyl-4H-pyridino[3,2-d]-m-dioxin(1.5 g, 5.5 mmol) and 5% Pd/C catalyst (0.3 g) yield the title compound1.0 g (82.8%) after recrystallisation from methanol/diethyl ether, as awhite crystalline solid m.p. 139-140° C. ¹H-NMR (DMSO-d₆) δ: 1.3-1.9 (m,6H, CHCH₃& N—CH₂CH₃, 4.6 (q, 2H, N—CH₂CH₃), 5.55 (q, 1H, CHCH₃), 7.4 (d,1H, 5-H(pyridinone)), 8.25 (d, 1H, 5-H(pyridinone)), 8.5-10.5 (br., 3H,OH) Anal. Calcd. for C₉H₁₄NO₃Cl: C, 49.21; H, 6.42; N, 6.38%. Found: C,49.30; H, 6.44; N, 6.30%

EXAMPLE 35 1-(3-hydroxypropyl)-2-hydroxymethyl-3-hydroxy-pyridin-4(1H)-one hydrochloride

[0134] In an analogous hydrogenation procedure in the preparation of1-methyl-2-hydroxymethyl-3-hydroxy-pyridin-4 (1H)-one hydrochloride,using8-oxo-4,8-dihydro-2-phenyl-5-(3-hydroxypropyl)-4H-pyridino[3,2-d]-m-dioxin(1.44 g, 5 mmol) and 5% Pd/C catalyst (0.3 g) yield the title compound0.98 g (83.2%) after recrystallisation from methanol/diethyl ether, as awhite crystalline solid. m.p. 138-139° C. ¹H-NMR (D₂O) δ: 1.9-2.6 (m,2H, N—CH₂CH₂CH₂O), 3.75 (t, 2H, N—CH₂CH₂CH₂O), 4.6 (m, 4H,N—CH₂CH₂CH₂O), 5.08 (s, 2H, CH₂O), 7.25 (d, 1H, 5-H(pyridinone)), 8.2(d, 1H, 6-H(pyridinone)) Anal. Calcd. for C₉H,₄NO₄Cl: C, 45.87; H, 5.99;N, 5.94%. Found: C, 45.87; H, 6.02; N, 5.75%

EXAMPLE 36 1-(3-hydroxypropyl)-2-(1-hydroxyethyl)-3-hydroxy-pyridin-4(1H)-one hydrochloride

[0135] In an analogous hydrogenation procedure in the preparation of1-methyl-2-hydroxymethyl-3-hydroxy-pyridin-4 (1H)-one hydrochloride,using 8-oxo-4,8-dihydro-2-phenylmethyl-5-(3-hydroxypropyl)4H-pyridino[3,2-d]-m-dioxin (1.3 g, 4.3 mmol) and 5% Pd/C catalyst (0.3 g) yieldthe title compound 0.88 g (82%) after recrystallisation frommethanol/diethyl ether, as a yellow crystalline solid. m.p. 117-120° C.¹H-NMR (DMSO-d₆) δ: 1.5 (d, 3H, CHCH₃), 1.65-2.45 (m, 2H, N—CH₂CH₂CH₂O),3.45 (t, 2H, N—CH₂CH₂CH₂O), 4.65 (m, 4H, N—CH₂CH₂CH₂O), 5.5 (s, 2H,CHCH₃), 7.3 (d, 1H, 5-H(pyridinone)), 8.18 (d, 1H, 6-H(pyridinone)),7.3-9.4 (br., 4H, OH) Anal. Calcd. for C₉H₁₄NO₄Cl: C, 48.10; H, 6.46; N,5.61%. Found: C, 48.39; H, 6.32; N, 5.62%.

ORALLY ACTIVE PRODRUG OF THE INVENTION EXAMPLE 371-[(3-Benzoyloxy)propyl]-2-hydroxymethyl-3-hydroxy-pyridin-4 (1H)-onehydrochloride (Ester prodrug of the invention).

[0136] 8-Oxo-4,8-dihydro-2-phenyl-5-[(3-benzoyloxy)propyl]-4H-pyridino[3,2-d]-m-dioxin (4.1 g, 10 mmol) was dissolved in 50 ml of DMF andadjusted to pH 1 with concentrated hydrochloric acid prior tohydrogenolysis for 6 hours in the presence of 5% Pd/C catalyst (1.0 g).Filtration followed by rotary evaporation in vacuo gave the crudeproduct as a white solid. Recrystallization from methanol/diethyl ethergave the pure title compound (2.9 g, 85%) as a white crystalline solid.m.p. 142-143° C. ¹H-NMR (DMSO-d₆) δ: 1.9-2.8 (m, 2H, N—CH₂CH₂CH₂O),4.0-5.0 (m, 4H, N—CH₂CH₂CH₂O), 4.8 (s, 2H, CH₂O), 7.2-8.1 (m, 6H, Ar &5-H(pyridinone)), 8.3 (d, 1H, 6-H(pyridinone)), 8.5-10.2 (br., 3H, OH)Anal. Calcd. for Cl₆H₈NO₅Cl: C, 56.56; H, 5.34; N, 4.12%. Found: C,56.40; H, 5.26; N, 4.08%

DE-ALKYLATED ACTIVE METABOLITES OF ORALLY ACTIVE COMPOUNDS OF THEINVENTION EXAMPLE 381-Ethyl-2-hydroxymethyl-3-hydroxy-6-methyl-pyridin-4 (1H)-onehydrochloride

[0137] 1.3 g (4 mmol)1-ethyl-2-methoxymethyl-3-benzyloxy-6-methyl-pyridin-4 (1H)-onehydrochloride was added to 40 ml of 4N hydrochloric acid and refluxedfor 6 hours. Concentration to dryness in vacuo afforded the crudeproduct. Recrystallisation from methanol/diethyl ether gave the puretitle compound (0.7 g, 80%) as a yellow crystalline solid. m.p. 160-162°C. ¹H-NMR (DMSO-d₆) δ: 1.3 (t, 3H, N—CH₂CH₃), 2.5 (s, 3H, 6-CH₃), 4.3(q, 2H, N—CH₂CH₃), 4.6 (s, 2H, 2-CH₂O), 7.1 (s, 1H, 5-H(pyridinone)),7.8-10.0 (br., 3H, OH) Anal. Calcd. for C₉H₁₄NO₃Cl⁻¹/₄H₂O: C, 48.22; H,6.52; N, 6.25%. Found: C, 48.44; H, 6.37; N, 6.15%

EXAMPLE 39 1-Ethyl-2-hydroxymethyl-3-hydroxy-pyridin-4 (1onehydrochloride

[0138] 2.0 g (7.33 mmol) 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one was dissolved in 50 ml of 4N hydrochloric acid and refluxed for6 hours. Concentration to dryness in vacuo afforded the crude product.Recrystallisation from methanol/diethyl ether gave the pure titlecompound (1.1 g, 73%) as a white crystalline solid. m.p. 168-169° C.¹H-NMR (D₂O) δ: 1.45 (t, 3H, N—CH₂CH₃), 4.4 (q, 2H, N—CH₂CH₃), 4.88 (s,2H, 2-CH₂O), 7.1 (d, 1H, 5-H(pyridinone)), 8.1 (d, 1H, 6-H(pyridinone))Anal. Calcd. for C₈H₁₂NO₃Cl: C, 46.73; H, 5.88; N, 6.81%. Found: C,46.71; H, 5.97; N, 7.01%.

ORALLY ACTIVE PRODRUGS OF THE INVENTION EXAMPLE 401,6-Dimethyl-2-methoxymethyl-3-hydroxy-pyridin-4 (1H)-one hydrochloride

[0139] 1,6-Dimethyl-2-methoxymethyl-3-benzyloxy-pyridin-4 (1H)-onehydrochloride (1.55 g, 5 mmol) was dissolved in methanol (40 ml)/water(10 ml) and hydrogenated for 4 hours in the presence of 5% Pd/C (0.3 g).Following filtration the filtrate was concentrated in vacuo and thecrude material recrystallised from methanol/diethyl ether gave the puretitle compound (0.95 g, 86.5%) as a white crystalline solid. m.p.156-159° C. ¹H-NMR (DMSO-d₆) 8: 2.53 (s, 3H, 6-CH₃), 3.28 (s, 3H, OCH₃),3.83 (s, 3H, N—CH₃), 4.68 (s, 2H, 2-CH₂OCH₃), 7.25 (s, 1H,5-H(pyridinone)), 6.0-8.5 (br., 2H, OH) Anal. Calcd. for C₉H₁₄NO₃Cl: C,49.21; H, 6.42; N, 6.38%. Found: C, 49.33; H, 6.49; N, 6.16%

EXAMPLE 41 1,6-Dimethyl-2-(1-methoxyethyl)-3-hydroxy-pyridin-4(1H)-onehydrochloride

[0140] In an analogous hydrogenation procedure in the preparation of1,6-dimethyl-2-methoxymethyl-3hydroxy-pyridin-4 (1H)-one hydrochlorideusing 1,6-dimethyl-2-(1methoxyethyl)-3-benzyloxy-pyridin-4 (1H)-onehydrochloride (1.62 g, 5 mmol) and 5% Pd/C catalyst (0.35 g) yield thetitle compound 1.06 g (90%/) after recrystallisation frommethanol/diethyl ether, as a white crystalline solid. m.p. 205-207° C.¹H-NMR (DMSO-d₆) 8: 1.5 (d, 3H, CHCH₃), 2.56 (s, 3H, 6-CH₃), 3.24 (s,3H, OCH₃), 4.05 (s, 3H, N—CH₃), 5.4 (q, 1H, CHCH₃), 7.4 (s, 1H,5H(pyridinone)), 8.5-10.0 (br., 2H, OR) Anal. Calcd. for C₁₀H₁₆NO₃Cl: C,51.40; H, 6.90; N, 5.99%. Found: C, 51.61; H, 6.76; N, 5.89%

EXAMPLE 42 1-Ethyl-2-(methoxymethyl-3-hydroxy -pyridin-4 (1H)-onehydrochloride

[0141] In an analogous hydrogenation procedure in the preparation of1,6-dimethyl-2-methoxymethyl-3-hydroxy-pyridin-4 (I 1H)-onehydrochloride using1-ethyl-2-methoxymethyl-3-benzyloxy-6-methyl-pyridin-4 (1H)-onehydrochloride (1.3 g, 4 mmol) and 5% Pd/C catalyst (0.3 g) yield thetitle compound 0.78 g (83%) after recrystallisation frommethanol/diethyl ether, as a white crystalline solid. m.p. 174-176° C.¹H-NMR (DMSO-d₆) δ: 1.47 (t, 3H, N—CH₂CH₃), 2.7 (s, 3H, 6-CH₃), 3.4 (s,3H,OCH₃), 4.4 (q, 2H, N—CH₂CH₃), 4.76 (s, 2H, 2-CH₂OCH₃), 7.35 (s, 1H,5-H(pyridinone))Anal. Calcd. for C₁₀H₁₆NO₃Cl: C, 51.40; H, 6.90; N,5.99%. Found: C, 51.31; H, 7.11; N, 6.04%

EXAMPLE 43 1,6-Dimethyl-2-(1-methoxypropyl)-3-hydroxy-pyridin-4 (1H)-onehydrochloride

[0142] 1,6-Dimethyl-2-(1-methoxypropyl)-3-benzyloxy-pyridin-4 (1H)-one(1.65 g, 5.5 mmol) was dissolved in methanol (30 ml)/water (10 ml) andadjusted to pH 1 with concentrated hydrochloric acid prior tohydrogenolysis for 4 hours in the presence of 5% Pd/C catalyst (0.35 g).Filtration followed by rotary evaporation gave the crude product as awhite solid. Recrystallization from methanol/diethyl ether gave the puretitle compound (1.08 g, 79.3%) as a white crystalline solid. m.p.225-227° C. ¹H-NMR (DMSO-d₆) δ: 0.9 (t, 3H, CHCH₂CH₃), 1.4-2.3 (m, 2H,CHCH₂CH₃), 2.6 (s, 3H, 6-CH₃), 3.28 (s, 3H, OCH₃), 4.04 (s, 3H, N—CH₃),5.15 (t, 1H, CHCH₂CH₃), 7.4 (s, 1H, 5-H (pyridinone)) Anal. Calcd. forC₁₁H₁₈NO₃Cl: C, 53.33; H, 7.32; N, 5.65%. Found: C, 53.30; H, 7.18; N,5.56%

EXAMPLE 44 1,6-Dimethyl-2-(1-ethoxyethyl)-3-hydroxy-pyridin-4 (1H)-onehydrochloride

[0143] 1,6-Dimethyl-2-(1-ethoxymethyl)-3-benzyloxy-pyridin-4 (1H)-one(3.65 g, 12 mmol) was dissolved in 40 ml of ethanol and adjusted to pH Iwith concentrated hydrochloric acid prior to hydrogenolysis for 4 hoursin the presence of 5% Pd/C catalyst (0.8 g). Filtration followed byrotary evaporation gave the crude product as a white solid.Recrystallization from ethanol/diethyl ether gave the pure titlecompound (2.48 g, 83.3%) as a white crystalline solid. m.p. 195-199° C.¹H-NMR (CDCl₃) 8: 1.2 (t, 3H, OCH₂CH₃), 1.6 (d, 3H, CHCH₃), 2.65 (s, 3H,6-CH₃), 3.5 (q, 2H, OCH₂CH₃), 4.1 (s, 3H, N—CH₃), 5.5 (q, 1H, CHCH₃),7.4 (s, 1H, 5-H(pyridinone)) Anal. Calcd. for C₁₁H₁₈NO₃Cl: C, 53.33; H,7.32; N, 5.65%. Found: C, 53.46; H, 7.16; N, 5.56%

NOVEL INTERMEDIATES FOR SYNTHESIS OF AMIDE COMPOUNDS OF THE INVENTIONEXAMPLE 45 2-Formyl-3-benzyloxy-6-methyl-pyran-4(1H)-one

[0144] To a solution of 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (5.28 g, 21.5 mmol, 1 eq) in 100 ml chloroform was added 27 mlof dimethyl sulfoxide and 18.5 ml of triethylamine and the reactionmixture was cooled with an ice-bath to an internal temperature of 3-5°C. Then sulfur trioxide pyridine complex (17.1 g 107 mmol, 5 eq) wasadded and the mixture was allowed to thaw to room temperature. Afterstirring for overnight at room temperature, the reaction mixture waswashed with water (2×50 ml) and the organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo to yield an organe oil. Furtherpurification by column chromatography on silica gel (eluant: Et2O)furnished the pure product (4.6 g, 87.7%) as a white crystalline solid.m.p. 78-81° C. ¹H-NMR (CDCl₃) δ: 2.3 (s, 3H, 6-CH₃), 5.4 (s, 2H, CH₂Ph),6.2 (s, 1H, 5-H(pyranone)), 7.28 (s, 5H, Ar), 9.75 (s, 1H, CHO) Anal.Calcd. for C₁₄H₁₂O₄: C, 68.84; H, 4.95%. Found: C, 68.96; H, 5.07%

EXAMPLE 46 2-Carboxy-3-benzyloxy-6-methyl-pyran-4(1H)-one

[0145] 2-Formyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (3.67 g, 15.03mmol, 1 eq) was dissolved in acetone (50 ml) and the solution dilutedwith water (50 ml). To the reaction mixture was added sulfamic acid(2.04 g, 21.04 mmol, 1.4 eq) and 80% sodium chlorite (1.78 g, 15.8 mmol,1.05 eq) and allowed to stir for 1 hour at room temperature in an openvessel. Removal of acetone in vacuo yielded crude product as aprecipitate in the remaining aqueous solution. The solid was collected,washed with absolute ethanol and dried (3.32 g, 85%). m.p. 173-175° C.¹H-NMR (DMSO-d₆) δ: 2.32 (s, 3H, 6-CH₃), 5.18 (s, 2H, CH₂Ph), 6.2 (s,1H, 5-H(pyranone)), 7.1-7.6 (m, SH, Ar) Anal. Calcd. for C₁₄H₁₂O₅: C,64.6; H, 4.6%. Found: C, 64.7; H, 4.9%

EXAMPLE 47 3-(2-Carbonyl-3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-1,3-thiazolidine-2-thione

[0146] 2-Carboxy-3-benzyloxy-6-methyl-pyran-4 (1H)-one (2.78 g, 10 mmol,1 eq) was dissolved in 100mi dichloromethane and the solution stirredvigorously. Dicyclohexylcarbodiimide (DCCI) (2.3 g, 11 mmol, 1.1 eq) wasthen added followed by the addition of 2-- mercaptothiazoline (1.32 g,11 mmol, 1.1 eq) and a catalytic amount of 4-dimethylaminopyridine(DMAP) (50 mg). The mixture was stirred for 24 h, the white precipitateN,N′-dicyclohexylurea (DCU) filtered from the yellow solution and thefiltrate volume was adjusted to 200 ml with CH₂Cl₂. The dichloromethanelayer was washed with 3×100 ml 0.1N sodium hydroxide solution, 100 mlwater, dried (Na₂SO₄), and concentrated in vacuo to yield the crudeproduct as a yellow oil. Further purification by column chromatographyon silica gel (eluant: EtOAc) furnished the pure product as a brightyellow oil (2.56 g, 71%). ¹H-NMR (CDCl₃) δ: 2.28 (s, 3H, 6-CH₃), 3.1 (t,2H, CH₂N), 4.35 (t, 2H, CH₂S), 5.3 (s, 2H, CH₂Ph), 6.25 (s, 1H,5-H(pyranone)), 7.28 (s, 5H, Ar) Anal. Calcd. for C₁₇H₁₅NO₄S₂: C, 56.49;H, 4.18%. Found: C, 56.98; H, 4.52%

EXAMPLE 48 3-Benzyloxy-6-methyl-4(1l)-pyranone-2-carboxy-(N-methyl)-amide

[0147] To a solution of 3-(2-carbonyl-3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-1,3-thiazolidine-2-thione (3.61 g, 100 mmol, 1 eq) in100 ml dichloromethane wad added  ml (20 mmol, 2 eq.) of 2M methylaminein THF and the reaction mixture allowed to stir for 2h. Thedichloromethane layer was washed with 3×50 ml 0.1N sodium hydroxidesolution, 50 ml water, dried (Na₂SO₄), and the solvent removed in vacuo.The crude product was further purified by column chromatography onsilica gel (eluant: EtOAc) furnished the pure product as a light yellowoil (2.4 g, 88%). ¹H-NMR (CDCl₃) δ: 2.3 (s, 3H, 6-CH₃), 2.7 (d, 3H,CH₃NH), 5.28 (s, 2H, CH₂Ph), 6.27 (s, 1H, 5-H (pyranone)), 7.3 (s, 5H,Ar)

EXAMPLE 49 3-Benzyloxy-6-methyl-4(1H)-pyranone-2-carboxy-(N-isopropyl)-amide

[0148] In an analogous procedure in the preparation of3-benzyloxy-6-methyl-4 (1H)-pyranone-2-carboxy-(N-methyl)-amide usingisopropylamine (1.5 eq) yielded the title compound as a yellow oil.Further purification by column chromatography on silica gel (eluant:EtOAc) furnished the pure product as a light yellow oil (yield 88%).¹H-NMR (CDCl₃) δ: 1.0 (d, 6H, CH(CH₃)₂), 2.4 (s, 3H, 6-CH₃), 3.7-4.5 (m,1H, CHNH), 5.4 (s, 2H, CH₂Ph), 6.25 (s, 1H, 5-H(pyranone)), 7.4 (s, 5H,Ar)

EXAMPLE 50 3-Benzyloxy-6-methyl-4(1H)-pyranone-2-carboxy-(N-2′-methoxyethyl)-amide

[0149] In an analogous procedure in the preparation of3-benzyloxy-6-methyl-4 (1H)-pyranone-2-carboxy-(N-methyl)-amide using2-methoxyethylamine (1.5 eq) yielded the title compound afterpurification by column chromatography on silica gel (eluant: EtOAc) as alight yellow oil (yield 94%). ¹H-NMR (CDCl₃) 8: 2.25 (s, 3H, 6-CH₃), 3.2(s, 3H, OCH₃), 3.0-3.6 (m, 4H, CH₂CH), 5.28(s, 2H, CH₂Ph), 6.1 (s, 1H,5-H(pyranone)), 7.26 (s, 5H, Ar), 7.5-8.2 (br., 1H, NH)

EXAMPLE 51 3-Benzyloxy-6-methyl-4(1H)-pyranone-2-carboxy-(N-2′-hydroxyethyl)-amide

[0150] In an analogous procedure in the preparation of3-benyloxy-6-methyl-4 (1H)-pyranone-2-carboxy-(N-methyl)-amide using2-hydroxyethylamine (1.5 eq) yielded the title compound afterpurification by column chromatography on silica gel (eluant: EtOAc) as alight yellow oil (yield 90%). ¹H-NMR (CDCl₃) δ: 2.3 (s, 3H, 6-CH₃),3.1-3.8 (m, 4H, CH₂CH₂), 5.29 (s, 2H, CH₂Ph), 6.15 (s, 1H,5-H(pyranone)), 7.3 (s, 5H, Ar), 7.5-8.2 (br., 1H, NH)

EXAMPLE 52 3-benzyloxy-6-methyl-4(1l)-pyranone-2-carboxy-(N,N-dimethyl)-amide

[0151] In an analogous procedure in the preparation of3-benzyloxy-6-methyl-4 (1H)-pyranone-2-carboxy-(N-methyl)-amide using 2Mdimethylamine in THF (3 eq) yielded the title compound afterpurification by column chromatography on silica gel (eluant: EtOAc) as alight yellow oil (yield 88%). ¹H-NMR (CDCl₃) δ: 2.31 (s, 3H, 6-CH₃),2.88 (s, 3H, CH₃N), 3.03 (s, 3H, CH₃N), 5.2 (s, 2H, CH₂Ph), 6.22 (s, 1H,5-H(pyranone)), 7.35 (s, 5H, Ar)

ORALLY ACTIVE PRODRUGS OF THE INVENTION EXAMPLE 531,6-Dimethyl-3-benzyloxy-4 (1H)-pyridinone -2-carboxy-(N-methyl)-amide

[0152] To a solution of 3-benzyloxy-6-methyl-4(1H)-pyranone-2-carboxy-(N-methyl)-amide (1.37 g, 5 mmol, 1 eq.) inmethanol (10 ml) was added 20 ml (40 mmol, 8 eq.) of 2M methylamine inmethanol. The reaction mixture was sealed in a thick-walled glass tubeand stirred at 70° C. for 12 hours. After removal of the solvent, theresidue was purified by column chromatography on silica gel (eluant: 12%CH₃OH/88% CHCl₃) furnished the pure product (1.1 g, 76.9%) as a whitecrystalline solid. m.p. 164-165.5° C. ¹H-NMR (CDCl₃) δ: 2.2 (s, 3H,6-CH₃), 2.65 (d, 3H, CH₃NH), 3.47 (s, 3H, N—CH₃), 4.92(s, 2H, CH₂Ph),5.95 (s, 1H, 5-H(pyridinone)), 7.28 (s, 5H, Ar), 7.9-8.4 (br, 1H, NH)

EXAMPLE 54 1,6-Dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-isopropyl)-amide

[0153] In an analogous procedure in the preparation of1,6-dimethyl-3-benzyloxy-4 (1H)-pyridinone-2-carboxy-(N-methyl)-amideusing 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-(N-isopropyl)-amide yielded the crude product.Further purification by column chromatography on silica gel (eluant: 10%CH₃OH/90% CHCl₃) afforded the pure title compound as a pale yellowcrystalline solid (yield, 79%) m.p. 176-178° C. ¹H-NMR (CDCl₃) δ: 1.2(d, 6H, CH(CH₃)D, 2.1 (s, 3H, 6-CH₃), 3.48 (s, 3H, N—CH₃), 3.9-4.5 (m,1H, CHNH), 4.98 (s, 2H, CH₂Ph), 5.98 (s, 1H, 5-H(pyridinone)), 7.22 (s,5H, Ar), 8.0-8.4 (br, 1H, NH)

EXAMPLE 55 1,6-Dimethyl-3-benzyloxy-4 (1H)-pyridinone-2-carboxy-(N-2′-methoxyethyl)-amide

[0154] In an analogous procedure in the preparation of1,6-dimethyl-3-benzyloxy-4 (1H)-pyridinone-2-carboxy-(N-methyl)-amideusing 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-(N-2′-methoxyethyl)-amide yielded the puretitle compound after purification by column chromatography on silica gel(eluant: 10% CH₃OH/90% CHCl₃) afforded as a white crystalline solid(yield, 82%) m.p. 125-126° C. ¹H-NMR (CDCl₃) δ: 2.1 (s, 3H, 6-CH₃), 3.2(s, 3H, OCH₃), 3.1-3.7 (m, 4H, CH₂CH₂), 3.42 (s, 3H, N—CH₃), 4.95 (s,2H, CH₂Ph), 6.02 (s, 1H, 5-H(pyridinone)), 7.0-7.5 (m, 5H, Ar), 7.8-8.4(br, 1H, NH)

EXAMPLE 56 1,6-Dimethyl-3-benzyloxy-4 (1H)-pyridinone-2-carboxy-(N-2′-hydroxyethyl)-amide

[0155] In an analogous procedure in the preparation of1,6-dimethyl-3-benzyloxy-4 (1H)-pyridinone-2-carboxy-(N-methyl)-amideusing1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-(N-2′-hydroxyethyl)-amideyielded the pure title compound after purification by columnchromatography on silica gel (eluant: 15% CH₃OH/85% CHCl₃) afforded as awhite crystalline solid (yield, 86%) m.p. 153-155° C. ¹H-NMR (CDCl₃) 3:2.1 (s, 3H, 6-CH₃), 3.1-3.7 (m, 4H, CH₂CH), 3.42 (s, 3H, N—CH₃), 4.95(s, 2H, CH₂Ph), 6.02 (s, 1H, 5-H(pyridinone)), 7.0-7.5 (m, 5H, Ar),7.8-8.4 (br, 1H, NH)

EXAMPLE 57 1,6-Dimethyl-3-benzyloxy-4 (1H)-pyridinone-2-carboxy-(N,N-dimethyl)-amide

[0156] In an analogous procedure in the preparation of1,6-dimethyl-3-benzyloxy-4 (1H)-, pyridinone-2-carboxy-(N-methyl)-amideusing 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-(N,N-dimethyl)-amide yielded the pure titlecompound after purification by column chromatography on silica gel(eluant: 10% CH₃OH/90% CHCl₃) afforded as a yellow oil (yield, 46%)¹H-NMR (CDCl₃) δ: 2.3 (s, 3H, 6-CH₃), 2.8 (s, 3H, CH₃N), 3.0 (s, 3H,CH₃N), 3.42 (s, 3H, N—CH₃), 5.2 (q, 2H, CH₂Ph, AB center), 6.3 (s, 1H,5-H(pyridinone)), 7.0-7.5 (m, 5H, Ar)

EXAMPLE 58 1,6-Dimethyl-3-hydroxy-4(1H)-pyridinone-2-carboxy-(N-methyl)-amide hydrochloride

[0157] 0.86 g of 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-(N-methyl)-amide was dissolved in 30 ml of DMFand hydrogenated at room temperature for 3 hours in the presence of 5%Pd/C catalyst (0.2 g). The catalyst was removed by filtration and thefiltrate was acidified to pH I with concentrated hydrochloric acidfollowed by rotary evaporation in vacuo gave the crude product as awhite solid. Recrystallization from methanol/diethyl ether gave the puretitle compound (0.65 g, 93%) as a white crystalline solid. m.p. 238° C.(dec.) ¹H-NMR (DMSO-d₆) δ: 2.5 (s, 3H, 6-CH₃), 2.7 (d, 3H, CH₃NH), 3.7(s, 3H, N—CH₃), 7.2(s,1H, 5-H(pyridinone)), 6.8-8.1 (br, 2H, OH),8.7-9.2 (br, 1H, NH) Anal. Calcd. for C₉H₁₃ClN₂O₃: C, 46.42; H, 5.59; N,12.03% Found: C, 46.28; H, 5.71; N, 11.86%

EXAMPLE 59 1,6-Dimethyl-3-hydroxy-4 (1H)-pyridinone-2-carboxy-(N-isopropyl)-amide hydrochloride

[0158] An analogous hydrogenation procedure to the preparation of1,6-dimethyl-3-hydroxy-4 (1H)-pyridinone-2-carboxy-(N-methyl)-amidehydrochloride, using 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-(N-isopropyl)-amide and 5% Pd/C catalystyielded the title compound (yield, 93%) after recrystallisation frommethanol/diethyl ether, as a white crystalline solid. m.p. 219-220° C.¹H-NMR (DMSO-d₆) δ: 1.18 (d, 6H, CH(CH₃)2), 2.52 (s, 3H, 6-CH₃), 3.7 (s,3H, N—CH₃), 3.64.4 (m, 1H, CHNH), 5.2-6.5 (br, OH), 7.3 (s, 1H,5-H(pyridinone)), 8.8-9.2 (br, 1H, NH) Anal. Calcd. for C₁₁H₁₇ClN₂O₃: C,50.63; H, 6.52; N, 10.74% Found: C, 50.38; H,. 6.81; N, 10.56%

EXAMPLE 60 1,6-Dimethyl-3-hydroxy-4(1H)-pyridinone-2-carboxy-(N-2′-methoxyethyl)-amide hydrochloride

[0159] An analogous hydrogenation procedure to the preparation of1,6-dimethyl-3-hydroxy-4 (1H)-pyridinone-2-carboxy-(N-methyl)-amidehydrochloride, using 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-(N-2′-methoxyethyl)-amide yielded the titlecompound (yield, 90%) after recrystallisation from methanol/diethylether, as a white crystalline solid. m.p. 204-206° C. ¹H-NMR (DMSO-d₆)δ: 2.6 (s, 3H, 6-CH₃), 3.4 (s, 3H, OCH₃), 3.1-3.6 (m, 4H, CH₂CH₂), 3.8(s, 3H, N—CH₃), 7.35 (s, 1H, 5-H(pyridinone)), 8.8-10.05 (br, OH & NH)Anal. Calcd. for C, H₁₇ClN₂O₄: C, 47.70; H, 6.14; N, 10.12% Found: C,47.56; H, 6.30; N, 10.36%

EXAMPLE 61 1,6-Dimethyl-3-hydroxy-4(1H)-pyridinone-2-carboxy-(N-2′-hydroxyethyl)-amide hydrochloride

[0160] An analogous hydrogenation procedure to the preparation of1,6-dimethyl-3-hydroxy-4 (1H)-pyridinone-2-carboxy-(N-methyl)-amidehydrochloride, using 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-(N-2′-hydroxyethyl)-amide yielded the titlecompound (yield, 91%) after recrystallisation from methanol/diethylether, as a white crystalline solid. m.p. 178-181° C. ¹H-NMR (DMSO-d₆)δ: 2.55 (s, 3H, 6-CH₃), 3.1-3.7 (m, 4H, CH₂CH), 3.85 (s, 3H, N—CH₃),7.25 (s, 1H, 5-H(pyridinone)), 6.7-8.2 (br., OH), 9.1 (t, 1H, NH) Anal.Calcd. for C₁₀H₁₅OClN₂O₄: C, 45.68; H, 5.71; N, 10.66% Found: C, 45.47;H, 5.98; N, 10.48%

EXAMPLE 62 1,6-Dimethyl-3-hydroxy-4 (1H)-pyridinone-2-carboxy-(N,N-dimethyl)-amide hydrochloride

[0161] An analogous hydrogenation procedure to the preparation of1,6-dimethyl-3-hydroxy-4 (1H)-pyridinone-2-carboxy-(N-methyl)-amidehydrochloride, using 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-(N,N-dimethyl)-amide yielded the titlecompound (yield, 94%) after recrystallisation from methanol/diethylether, as a white crystalline solid. m.p. 219° C.(dec.) ¹H-NMR (DMSO-d6)δ: 2.5 (s, 3H,6-CH₃), 2.8 (s, 3H, CH₃N), 3.0 (s, 3H, CH₃N), 3.65 (s, 3H,N—CH₃), 7.25 (s, 1H, 5-H(pyridinone)), 7.5-9.0 (br., OH) Anal. Calcd.for C₁₀H₁₅ClN₂O₃: C, 48.64; H, 6.08; N, 11.35% Found: C, 48.58; H, 6.22;N, 11.08%

EXAMPLE 63 Formulation of medicaments

[0162] (A) Tablets of the following composition are prepared: mg/tabletCompound of formula (I) (micronised) 250 ‘Avicel’ (microcrystallinecellulose) 38 polyvinylpyrrolidone 3 alginic acid 6 magnesium stearate 3

[0163] The 3-hydroxypyridin-4-one is mixed with ‘Avicel’ andpolyvinylpyrrolidone is added, dissolved in sufficient industrialmethylated spirits (74° OP) to produce a mass suitable for granulating.The mass is granulated through a 20mesh sieve and the resultant granulesare dried at a temperature not exceeding 50° C. The dried granules arepassed through a 20 mesh sieve and the alginic acid and magnesiumstearate are then added and mixed with the granules. The product iscompressed into tablets each weighing 300 mg on ⅜ inch flat bevellededge divided punches.

[0164] (B) Tablets of the following composition are prepared: mg/tabletCompound of formula (I) (micronised) 250 ‘Avicel’ (microcrystallinecellulose) 134 polyvinylpyrrolidone 4 alginic acid 8 magnesium stearate4

[0165] The tablets are prepared by essentially the same procedure asdescribed in (A) and are compressed at a tablet weight of 400 mg on{fraction (7/16)} inch flat bevelled edge punches.C)

[0166] Tablets of the following composition are prepared: mg/tabletCompound of formula (I)(micronised) 250 lactose (300 mesh) 19 maizestarch 15 gelatine 10 magnesium stearate 6

[0167] The 3-hydroxypyridin-4-one is mixed with lactose and half thetotal quantity of maize starch required, and a 5% solution of gelatinein water is added to the mass. The product is granulated through a 16mesh sieve, and the resultant granules are dried to constant weight at atemperature not exceeding 50° C. The dried granules are passed through a20 mesh sieve and mixed with magnesium stearate and the remainder of themaize starch. The product is compressed at a 300 mg tablet weight on3/8inch flat bevelled edge divided punches.

EXAMPLE 64 Iron III Mobilisation Efficacy Assay in Rat: OralAdministration

[0168] Hepatocytes of manually fasted rats (190-230 g) were labelledwith 10 μg ⁵⁹Fe ferritin 10injected iv into the tail vein. One hourlater each rat was administered orally with a dose of chelator (150-450[mol/Kg: see Table 2 below). Control rats were given an equivalentvolume of water. The rats were placed in individual metabolic cages andtheir urine and faeces collected. One hour after the administration theywere allowed access to food, with no restriction on water being madethroughout the study period. The investigation was terminated 24 hoursafter the ⁵⁹Fe ferritin administration when rats were sacrificed andtheir livers and gastrointestinal tracts , including all contentsincluding faeces, were removed for gamma counting. Iron mobilisationefficiency is shown in Tables 1 to 3

TABLE 1 pM Iron Mobilisation Compound Structure D_(pH 7.4) pKa Logβ₃ pH7.45 (%) CP20*

0.17 3.56, 9.64 (s) 3.68, 9.77 (p) 36.3 19.4 10.7 ± 3.0% (n = 10) CP94*

1.79 3.81, 9.93 (p) 36.7 19.7 58.3 ± 9.4% (n = 10) CP41*

0.13 — — — 29.9 ± 4.3% (n = 5) CP359

0.14 2.88, 9.05 (s) 2.80, 9.27 (p) 35.25 20.96 33.3 ± 6.7% (n = 5) CP360

0.098 3.37, 9.42 (s) 3.32, 9.44 (p) 35.51 20.43  4.5 ± 1.1% (n = 5)CP361

0.25 3.55, 8.97 (s) 3.54, 8.99 (p) 35.52 21.47 48.4 ± 7.2% (n = 10)CP362

0.42 — — — 51.5 ± 3.7% (n = 5) CP363

1.09 3.22, 9.43 (s) 3.20, 9.44 (p) — — 73.5 ± 8.1% (n = 10) CP364

0.048 2.93, 9.12 (s) 3.13, 9.22 (p) 35.3 20.75 8.44 ± 3.6% (n = 5) CP365

0.27 3.11, 8.74 (s) 3.03, 8.77 (p) 34.8 21.3 54.5 ± 9.9% (n = 5) CP366

0.056 2.87, 9.14 (s) 3.02, 9.29 (p) 35.25 20.69 11.7 ± 4.1% (n = 5)CP367

5.61 2.70, 8.95 (s) 2.60, 9.07 (p) — — 56.0 ± 6.0% (n = 10) CP369

0.223 3.28, 9.38 (s) 3.29, 9.45 (p) 35.6 20.35 12.9 ± 2.3% (n = 5) CP370

1.08 — — — 41.6 ± 7.5% (n = 5) CP372

0.075 2.96, 8.69 (s) 2.98, 8.72 (p) 34.67 21.48 14.3 ± 4.5% (n = 5)CP373

3.32 — — — 39.5 ± 4.8% (n = 5) CP374

0.73 2.78, 8.98 (s) 2.76, 9.00 (p) 35.03 20.95 60.4 ± 15.6% (n = 5)CP375

3.85 — — — 72.0 ± 8.2% (n = 5)

[0169] TABLE 2 Efficacy studies with different doses Dose IronMobilisation Efficacy Chelator Structure (μmol/kg) (%) (%) Control — —3.87 ± 1.0 — CP20*

450 300 150 13.4 ± 5.2  9.2 ± 2.2  6.3 ± 2.1  9.5  5.4  2.4 CP94*

450 300 150 59.7 ± 10.9 35.7 ± 4.4 16.5 ± 6.2 55.8 31.8 12.6 CP363

450 300 150 73.5 ± 8.1 66.9 ± 8.7 (n = 5) 40.7 ± 2.4 (n = 5) 69.6 63.036.8 CP374

450 150 60.4 ± 15.6 34.0 ± 4.3 (n = 5) 56.5 30.1 CP375

450 150 72.0 ± 8.2 40.2 ± 8.5 (n = 5) 68.1 36.3

1. A novel 3-hydroxypyridinone compound of formula I is provided

wherein R is hydrogen or a group that is removed by metabolism in vivoto provide the free hydroxy compound, R¹ is an aliphatic hydrocarbongroup or an aliphatic hydrocarbon group substituted by a hydroxy groupor a carboxylic acid ester, sulpho acid ester or a C₁₋₆ alkoxy, C₆-aryloxy or C₇₋₁₀ aralkoxy ether thereof, R³ is selected from hydrogenand C₁₋₆ alkyl; characterized in that R² is selected from groups (i)—CONH—R⁵ (ii) —CR⁶R⁶OR⁷ (iii) —CONHCOR⁵ and (iv) —CON(CH₃)₂ R⁴ isselected from hydrogen, C₁₋₆ alkyl and a group as described in R²; R⁵ isselected from hydrogen and optionally hydroxy, alkoxy, or aralkoxysubstituted C₁₋₁₃ alkyl, aryl and C₇₋₁₃ aralkyl, R⁶ is independentlyselected from hydrogen, C₁₋₁₃ alkyl, and R⁷ is selected from hydrogen,C₁₋₁₃ alkyl, aryl and C₇₋₁₃ aralkyl or a pharmaceutically acceptablesalt of any such compound with the proviso that the compound is not oneof 1-ethyl-2-(1′-hydroxyethyl)-3-hydroxypyridin-4-one and1-methyl-2-hydroxymethyl-3-hydroxypyridoin-4-one
 2. A compound asclaimed in claim 1 characterised in that R completes a carboxylic orsulpho acid ester group with the oxygen shown, or is C₁₋₆ alkyl or C₇₋₁₀aralkyl.
 3. A compound as claimed in claim 2 characterised in that R₂ isa group —O—R⁶ or —OC(O)—R⁸ where R⁸ is C₁₋₆ alkyl or C₇₋₁₀ aralkyl.
 4. Acompound as claimed in any one of claims 1 to 3 characterized in that R⁵and R⁷ are independently selected from C₁₋₆ alkyl, aryl and C₇₋₁₀aralkyl.
 5. A compound as claimed in any one of claims 1 to 4characterised in that R⁶ is independently selected from hydrogen andC₁₋₆ alkyl.
 6. A compound as claimed in any one of claims 1 to 4characterized in that R⁶ is is an aliphatic carbon group substituted bya hydroxy group or an esterified hydroxy group, the ester acyl groupthereof being of formula —CO—R⁹ where R⁹ is C₁₋₆ alkyl or phenyl.
 7. Acompound as claimed in any one of the preceding claims characterised inthat R² is (a) a group —CR⁶R⁶OR⁷wherein R⁶ is independently selected ateach occurrence from hydrogen and C₁₋₁₃ alkyl, and R⁷ is C₁₋₆ alkyl or(b) a group —CONH—R⁵.
 8. A process for the preparation of a compound offormula (I) characterised in that it comprises the reaction of a2-(1-hydroxyalkyl)-3-hydroxy-pyran-4(1H)-one of formula (II)

with benzaldehyde dimethyl acetal to provide the corresponding8-oxo-4,8dihydro-2-phenyl-4H[3,2-d]-m-dioxin of formula (IIb),

reacting that compound with a compound R¹NH₂ to give the correspondingpyridino dioxin of formula (IIc)

and reducing that with hydrogen to give the corresponding2-hydroxyalkyl-pyran-4(1H)-one wherein R¹, R³ and R⁴ are as defined inclaim 1 and R¹⁰ is defined as for R⁶in claim
 1. 9. A process for thepreparation of a compound of formula (I) characterised in that itcomprises the protection of the 3-hydroxyl group of a2-(1-hydroxyalkyl)-3-hydroxy-pyran-4(1H)-one of formula (IV),

to give a compound (IVa)

alkylating the 2-(1-hydroxy) group to provide a compound (IVb)

and reacting the product (IVb) with a compound R¹NH₂ to provide thecorresponding 2-hydroxyalkyl-pyridin-4 (1H)-one (IVc)

wherein R¹, R³, R⁴ and R⁷ are as defined in claim 1 and R¹⁰ is definedas for R⁶in claim
 1. 10. A process as claimed in claim 9 characterisedin that the compound of formula (IVc) is reduced to provide thecorresponding unprotected compound.
 11. A process for the preparation ofa compound of formula (I) characterised in that it reacts a 2-carboxycompound of formula (IXd),

with mercaptothiazoline to provide the corresponding2-carbonyl-thiazolidine-2-thione of formula (X),

reacts that with a compound R⁵NH₂ to give the corresponding 2-amidocompound of formula (XI),

and reacts that with a compound R¹NH₂ to give the corresponding2-amido-pyridin-4 (1H)-one compound of formula (XII)

wherein R¹, R³, R⁴ and R⁵ are as defined in claim
 1. 12. A process asclaimed in claim 11 characterised in that it comprises reducing thecompound of formula (XII) to provide the corresponding2-hydroxyalkyl-pyridin-4(1l)-one.
 13. An8-oxo-4,8-dihydro-2-phenyl-4H[3,2-d]-m-dioxins of formula (IIb).

wherein R³ and R⁴ are as defined in claim 1 and R⁶ is defined as forR⁶in claim
 1. 14. A 2-(1-alkoxyoxyalkyl)-3-hydroxy-pyran-4 (1H)-onecompound of formula (IV).

wherein R³ and R⁴ are as defined in claim 1 and R¹⁰ is defined as forR⁶in claim 1 with the proviso that R¹⁰ is not H or CH₃ when R⁴ is CH₃and R¹⁰ is not H when R⁴is H or CH₃.
 15. A2-carbonyl-thiazolidine-2-thione of formula (X).

wherein R³ and R⁴ are as defined in claim 1
 16. A compound as claimed inany one of claim 1 to 7 or a pharmaceutically acceptable salt of anysuch compound for use in therapy.
 17. Use of a compound as claimed inany one of claims 1 to 7 or a pharmaceutically acceptable salt of anysuch compound in the manufacture of a medicament for the treatment of aniron associated disease.
 18. A pharmaceutical composition comprising acompound as claimed in any one of claims 16 to 17 together with apharmaceutically acceptable carrier.
 19. A composition as claimed inclaim 18 characterised in that it is in a form suitable for oraladministration.
 20. A composition as claimed in claim 19 characterisedin that it is in the form of a tablet, lozenge or capsule.